Transdermal delivery systems

ABSTRACT

Transdermal delivery systems for administering sufentanil through the skin are provided. The systems contain a sufficient amount of sufentanil to induce and maintain a constant state of analgesia when applied to a subject. The systems are characterized as having one or more features including a high degree of dosage form rate control over flux of sufentanil from the system, a high net flux of sufentanil from the system through the skin, lack of a permeation enhancer, an adhesive member demonstrating superior shear time, a low coefficient of variation in the net flux of sufentanil from the system, a high delivery efficiency, and a substantially constant steady state net flux of sufentanil from the system. Methods of using the transdermal delivery systems to administer a sufficient amount of sufentanil to induce and maintain analgesia for extended periods when applied to a subject are also provided.

This application is a continuation of co-pending U.S. application Ser.No. 11/665,813, filed on Apr. 19, 2007, herein incorporated byreference.

FIELD OF THE INVENTION

The invention relates generally to transdermal delivery systems, andmore particularly to transdermal delivery systems for administeringsufentanil through the skin. The transdermal delivery systems can beused to administer sufentanil to an individual over an extended periodof time to provide an analgesic effect.

BACKGROUND OF THE INVENTION

Many medications are used for the treatment of pain, ranging from wellknown, over-the-counter compounds such as aspirin, acetaminophen,ibuprofen and other non-steroidal anti-inflammatory compounds to thenewly developed chemical entities such as the cyclooxygenase IIinhibitor compounds. Opiates in various forms, including opium, heroineand morphine that derive from the opium poppy, have very powerfulanalgesic properties. Opiates have been widely used for anesthesia aswell for the treatment of pain, especially where the pain is verysevere. In addition to these natural opiates, many synthetic opioidshave since been synthesized including methadone, fentanyl and congenersof fentanyl such as sufentanil, alfentanil, lofentanil, carfentanil,remifentanil, etc. Of the opioids, morphine is still the drug of choicefor management of pain at least in part due to its low cost, the abilityof the drug to provide relief from pain of a variety of origins, and thevast experience with this drug. Despite its therapeutic advantages andvast experience with the drug, many pain management experts believe thatmorphine and other opioids are under-prescribed for patients who requirelong-term pain therapy.

One reason for under prescription is the risk of the side effectsassociated with long-term administration of opioids in general, such asdevelopment of opiate tolerance, dependence, constipation, and/or otherundesirable side effects (see, e.g., Moulin et al. (1992) Can Med.Assoc. J. 146:891-7). Patients who develop opioid tolerance requireincreased doses to achieve a satisfactory analgesic effect and risk thedevelopment of further

In one aspect of the invention, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

is at least about 50%, in other systems it is at least about 60%, and instill other systems, it is at least about 65% or greater. The dosageform rate control can be provided by a number of differentmechanisms/components, either alone or in combination. For example, ratecontrol can be provided at least in part by using a pharmaceuticallyacceptable adhesive matrix carrier composition. Alternatively, or inaddition, a rate controlling membrane can be used to provide controlover delivery of sufentanil from the system.

It is another object of the invention to provide a transdermal deliverysystem for administering sufentanil through the skin. The system is amatrix-type transdermal patch system, and includes a pressure-sensitiveadhesive matrix containing the sufentanil agent. The system does notcontain a permeation enhancer. The adhesive properties of the matrix areselected such that the system has a shear time of from about 1 to 40minutes as determined using the Shear Time Measurement Test.

In one aspect of the invention, the adhesive matrix provides dosage formrate control over flux of sufentanil from the system. In other aspects,the system is characterized by having a substantially high net flux ofsufentanil from the system. In this regard, certain systems provide anet flux of sufentanil from the system through the skin of at leastabout 1 μg/cm²/hour, while other systems provide a net flux of at leastabout 1.5 μg/cm²/hour. In certain systems, the overall size of thetransdermal delivery system is kept to minimum, such that the adhesivematrix has a drug releasing interface surface area of from about 1-10cm².

It is still another object of the invention to provide a transdermaldelivery system for administering sufentanil through the skin. Thesystem provides a dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system of at least about 50% whilestill allowing a net flux of sufentanil from the system through the skinof at least about 1 μg/cm²/hour. The system does not contain apermeation enhancer.

In one aspect of the invention, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is even higher, for example atleast about 60%, while in still other systems the dosage form ratecontrol is at least about 65%. In these systems, the dosage undesirableside effects such as respiratory depression, which can be lifethreatening. Physical dependence, which is related to factors such asthe dose administered and the length of the administration period, cangenerally only be resolved by discontinuing opioid administration, whichin turn results in the onset of severely painful withdrawal symptoms.Other side effects that can be associated with administration of opioidsinclude reduced cough reflex, bronchial spasms, nausea, vomiting,peripheral vasodilation, orthostatic hypotension, vagal impact on theheart, contraction of smooth muscles (sphincters), reduced peristalticmotility in the gastrointestinal tract (e.g., constipation), urinaryretention, changes in regulation of body temperature and sleep pattern,and release of histamine, adrenalin, and anti-diuretic hormone. Thenegative effects on respiratory function especially impact postoperativepatients, who are particularly susceptible to depression of respiratoryfunction. Even where the concerns regarding side effects might beoutweighed by the serious need for pain relief as in terminally illpatients, many doctors still avoid prescribing opioids due to concernsof abuse of surplus medication by others in contact with the patient, oreven that their frequent prescription of the drug might lead to criminalinvestigation.

In addition to the disadvantages listed above pertaining to opioids ingeneral, morphine itself has also been associated with particular sideeffects, at times so severe as to make such therapy intolerable,especially for patients who are on long-term pain therapy or who requirehigh doses of medication to obtain relief. Some of these side effectsassociated with morphine usage, particularly at high doses, includenausea and vomiting and severe constipation. In addition, Sjorgen et al.(1994 Pain 59:313-316) have reported the phenomena of hyperalgesia(increased response to certain stimulus which is not normally painful),allodynia (sensation of pain felt even when stimulus is not normallypainful) and myoclonus associated with morphine use. It has thus beenhypothesized that morphine and its metabolites may induce such abnormalsensitivity.

Fentanyl and its congeners were originally developed as anesthesiaagents, and are generally used in the United States for the limitedpurposes of intravenous administration in balanced general anesthesia,as a primary anesthetic, or, in the case of sufentanil, for epiduraladministration during labor and delivery. However, these drugs also havepowerful analgesic properties and are several hundred- to severalthousand-times more potent than morphine depending on the particularcongener. A few studies have in fact suggested that fentanyl and itscongeners be used instead of morphine due to their increased potency anddecreased side effects relative to morphine (see e.g., Sjorgen et al.(1994) Pain 59:313-316). Fentanyl and its congeners are, however, moredifficult to administer than morphine since they are not orallyabsorbed, are extremely potent (requiring very precise, accurate dosingof small amounts) and have very short half lives in the body thusrequiring frequent dosing. For these reasons, conventional methods fordelivery of opioid analgesics are deemed inadequate to meet thesedelivery requirements.

For example, fentanyl has been administered in single, small intravenousdoses, but this method of administration, besides being impractical forlong-term therapy, results in a short duration of action and rapidrecovery due to a redistribution into fat stores and a rapid decline inplasma concentration. While subcutaneous infusion of fentanyl andsufentanil have been the subject of experimentation on a limited basis,such infusion methods are impractical as long-term pain therapies. Forexample, subcutaneous fentanyl and sufentanil delivery has been used asan alternative therapy in a small number of patients who sufferedsignificant side effects associated with administration of morphine.Paix et al. (1995) Pain 63:263-9. In these therapies, the drug wasinfused into the subcutaneous space in relatively low drugconcentrations and at relatively large volume rates (e.g., on the orderof 3 mL/day to 40 mL/day) via an external syringe driver. Thesetreatment approaches have several major disadvantages that render themimpractical for long-term therapy. First, provision of drug from anexternal source adversely affects mobility of the patient and istherefore inconvenient for ambulatory patients, increases the risk ofinfections at the subcutaneous delivery site and provides an opportunityfor drug to be diverted for illicit uses. Second, the infusion of largevolumes of fluid may result in tissue damage or edema at the site ofinfusion. In addition, the absorptive capacity of the subcutaneous spacelimits the volume of fluid that can be delivered, and this volumetriclimitation can in turn limit the amount of drug that can beadministered.

As an alternative to conventional methods for delivering opioidanalgesics, transdermal patch technologies, and controlled releaseimplant technologies have been developed. For example, a fentanyltransdermal patch is commercially available (DURAGESIC®, JanssenPharmaceutica Products, Titusville, N.J.). The fentanyl patch isprovided as a three-day product for pain management applications, and isavailable in systems containing from 2.5 to 10 mg of the fentanyl agent.Although the product has enjoyed significant commercial success,inherent limitations in the transdermal patch technology employed by theproduct make it less than ideal as an alternative to conventionalsystems. Most significantly, the fentanyl patch provides a widelyvariable rate of fentanyl delivery to the skin over the three-dayapplication period, and there is furthermore a significant variation inthe dose of fentanyl delivered among patients. DURAGESIC® FentanylTransdermal System Package Insert, 2004. The product is therefore dosagetitrated to individual patients on the basis of a nominal flux (theaverage amount of fentanyl delivered to systemic circulation per houracross average skin) value.

In addition, an implantable osmotic pump sufentanil product is inlate-phase clinical testing (CHRONOGESIC®, Durect Corporation,Cupertino, Calif.). The sufentanil pump product is adapted for wholeimplantation, typically in the subcutaneous space, and thus avoids thedelivery variability limitations seen with existing transdermal systemsby eliminating the need to traverse the body's skin barrier. Thesufentanil pump is currently provided as a three-month product for painmanagement, and is being tested with systems containing from 9 to 40 mgof the sufentanil agent.

SUMMARY OF THE INVENTION

Transdermal delivery systems for administering sufentanil through theskin are provided. It is thus an object of the present invention toprovide a transdermal delivery system for administering sufentanilthrough the skin, wherein the system provides for a high delivery rateof sufentanil through the skin, with a concomitant low degree ofvariability in the delivery, wherein the system provides a high degreeof system control over delivery of the sufentanil agent.

It is more particularly an object of the invention to provide atransdermal delivery system for administering sufentanil through theskin, where the system provides a dosage form rate control over flux ofsufentanil from the system and a net flux from the system through theskin of at least about 1 μg/cm²/hour. The system does not contain apermeation enhancer. form rate control can be provided by a number ofdifferent mechanisms/components, either alone or in combination. Thus,the dosage form rate control can be provided at least in part by using apharmaceutically acceptable adhesive matrix carrier composition.Alternatively, or in addition, a rate controlling membrane can be usedto provide control over delivery of sufentanil from the system. Despitesuch a high degree of system control in the present systems, certainsystems are able to provide a net flux of sufentanil from the systemthrough the skin of at least about 1.5 μg/cm²/hour, while still otherscan provide a net flux of around 2 μg/cm²/hour, all without the use of apermeation enhancer.

It is a further object of the invention to provide a transdermaldelivery system for administering sufentanil through the skin, where thesystem is able to provide high net flux of sufentanil from the systemswithout the use of permeation enhancers and where the coefficient ofvariation in the net flux

$( \frac{\Delta \; J_{N}}{J_{D}} )$

is low, being held to about 50% or less. When applied to a subject, thesystem provides a net flux of sufentanil from the system through theskin of at least about 1 μg/cm²/hour with a very low degree ofvariability in the net flux from the system, such that the coefficientof variation in the net flux is about 50% or less. The system does notcontain a permeation enhancer.

In one aspect of the invention, the low variability system furtherprovides a dosage form rate control over flux of sufentanil form thesystem. More particularly, certain systems are further able to provide adosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system of at least about 50% whilestill providing a very low degree of variability in the net flux fromthe system. In certain systems, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is even higher, for example atleast about 60%, while in still other systems the dosage form ratecontrol is at least about 65%. The dosage form rate control can beprovided by a number of different mechanisms/components, either alone orin combination. Thus, the dosage form rate control can be provided atleast in part by using a pharmaceutically acceptable adhesive matrixcarrier composition and/or a rate controlling membrane. Despite such alow degree of variability in the net flux from the present systems,certain systems are able to provide an even higher net flux ofsufentanil from the system through the skin, on the order of at leastabout 1.5 μg/cm²/hour, while still others can provide a net flux ofaround 2 μg/cm²/hour, all without the use of a permeation enhancer.

It is yet a further object of the invention to provide a small sizedsystem that can be used to induce and maintain analgesia for 3 or moredays when applied to a subject, where the delivery efficiency at the endof the therapeutic period is at least about 50%, more preferably about60%, and more preferably 70%, that is, up to about 70% of the sufentanilis delivered to the subject over the course of three days. Accordingly,a transdermal delivery system for administering sufentanil through theskin is provided. The system includes a reservoir containing asufficient amount of sufentanil to induce and maintain analgesia for 3or more days when applied to a subject. The reservoir may be an adhesiveor non-adhesive matrix, and has a dry, non-hydrated thickness of about1.25 to 5 mils. The system provides a (drug) delivery efficiency of upto at least about 70% of the sufentanil from the reservoir at the end of3 or more days of application to a subject.

In one aspect of the invention, the reservoir contains a sufficientamount of sufentanil to induce and maintain analgesia for 5 or more dayswhen applied to a subject while maintaining a delivery efficiency of atleast about 70% at the end of the 5 days, and still other systemsinclude a reservoir that contains a sufficient amount of sufentanil toinduce and maintain analgesia for 7 or more days when applied to asubject while maintaining a delivery efficiency of at least about 70% atthe end of the 7 days. In certain other systems, the delivery efficiencyis at least about 80% at the end of the application period. It ispreferred that the overall system size of the instant high efficiencytransdermal delivery systems is minimized as much as possible.Accordingly, in certain aspects of the invention, the high efficiencysystems include a reservoir having a drug releasing interface surfacearea of from about 1-10 cm². In still further aspects, the highefficiency systems have a substantially small reservoir volume, forexample a volume of about 0.2 ml or less. In certain systems, thereservoir has a volume of from about 0.0025 to 0.154 ml.

It is another object of the invention to provide a monolithictransdermal delivery system, where the sufentanil is contained in anadhesive matrix adhered to a backing layer. Accordingly, a monolithictransdermal delivery system for administering sufentanil through theskin is provided. The system includes a pressure-sensitive adhesivematrix that contains sufentanil in an amount above the solubility ofsufentanil in the matrix. When the system is applied to a subject, thesystem provides a substantially constant steady state net flux ofsufentanil from the system through the skin of at least about 1μg/cm²/hour for at least about 24 hours. The system does not include apermeation enhancer or rate controlling membrane. It is a feature of theinvention that the systems are able to provide such high net fluxsystems that do not employ a permeation enhancer or rate controllingmembrane and can still perform to such high standards, where uponachieving steady state conditions, the system provides at least a firstorder release rate profile such that the system achieves substantiallyzero order release to provide a constant steady state flux of sufentanilfrom the system over an extended period of time. In certain systems, thesystem provides a substantially constant steady state net flux ofsufentanil from the system through the skin of at least about 1μg/cm²/hour for at least about 36 hours.

In one aspect of the invention, certain systems are also able to providean even higher steady state net flux net flux of sufentanil from thesystem through the skin, for example at least about 1.5 μg/cm²/hour insome systems, or even around 2 μg/cm²/hour in other systems. In certainsystems, the overall size of the transdermal delivery system is kept tominimum, such that the adhesive matrix has a drug releasing interfacesurface area of from about 1-10 cm².

It is a still further object of the invention to provide a monolithictransdermal delivery system for administering sufentanil through theskin. The system includes a pressure-sensitive adhesive matrix thatcontains sufentanil in an amount above the solubility of sufentanil inthe matrix. When the system is applied to a subject, the system providesa net flux of sufentanil from the system through the skin of at leastabout 1 μg/cm²/hour. The system provides a dosage form rate control overflux of sufentanil from the system, but the system does not include apermeation enhancer or rate controlling membrane. In these systems, thesufentanil is provided as a depot, and is thus present in the system inan amount above the solubility of sufentanil in the system, such thatthere will be both dissolved and undissolved sufentanil in the system.

In one aspect of the invention, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is at least about 50% whilestill providing the substantially high rate of net flux from the system.In certain systems, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is even higher, for example atleast about 60%, while in still other systems the dosage form ratecontrol is at least about 65%. The dosage form rate control can beprovided by a number of different mechanisms/components, either alone orin combination. Thus, the dosage form rate control can be provided atleast in part by using a pharmaceutically acceptable adhesive matrixcarrier composition and/or a rate controlling membrane. Despite notincluding a permeation enhancer or rate controlling membrane, certainsystems are able to provide an even higher net flux of sufentanil fromthe system through the skin, on the order of at least about 1.5μg/cm²/hour, while still others can provide a net flux of around 2μg/cm²/hour.

It is a still further object of the invention to provide a transdermaldelivery system for administering sufentanil through the skin of aliving subject, wherein the system provides a substantially constantdelivery rate of sufentanil over a single application administrationperiod of at least about 48 hours and the constant delivery rate issufficient to establish and maintain a plasma sufentanil concentrationhaving a minimum to maximum ratio of about 1.8 or less over the relevantadministration period.

In one aspect of the invention, the delivery rate of sufentanil from thetransdermal delivery system is substantially zero order. In otheraspects of the invention, the delivery rate of sufentanil ischaracterized by a total decline or increase of about 5 to 6% over theadministration period, and preferably, the delivery rate of sufentanilis characterized by substantially no total increase or decrease over theadministration period. The subject transdermal delivery systems are ableto provide a delivery rate at steady state of at least about 1 μg/hr to10 μg/hr, and the administration period is at least about 48 hours to 7days. In certain embodiments, the net flux from the system through theskin is at least about 1 μg/cm²/hour, and the system does not contain apermeation enhancer. In other aspects of the invention, the system has ashear time of from about 1 to 40 minutes as determined using the ShearTime Measurement test. In still further aspects, the system providesdosage form rate control (J_(N)/J_(D)) over flux of sufentanil from thesystem of at least about 50% and a net flux from the system through theskin of at least about 1 μg/cm²/hour. In other aspects, the systemprovides a net flux of sufentanil from the system through the skin of atleast about 1 μg/cm²/hour with a coefficient of variation (ΔJ_(N)/J_(N))of about 50% or less, or the system is a monolithic system comprising apressure-sensitive adhesive matrix containing sufentanil in an amountabove the solubility of sufentanil in the matrix, and the subject systemprovides a substantially constant steady state net flux of sufentanilfrom the system through the skin of at least about 1 μg/cm²/hour for atleast about 24 hours. In yet other aspects, system is a monolithicsystem including a pressure-sensitive adhesive matrix containing thesufentanil active agent in an amount above the solubility of sufentanilin the matrix, and the system provides a net flux from the systemthrough the skin of at least about 1 μg/cm²/hour, wherein a dosage formcontrol over flux of sufentanil from the system is provided by thesystem itself. Preferably, the above-described systems do not include apermeation enhancer or a rate controlling membrane.

It is an advantage of the present invention that the transdermaldelivery systems are able to provide sustained analgesia in a subjectfor from 3 to 7 days. It is a further advantage of the invention thatthe systems are readily constructed to provide any number of differentdosages and sizes, and further are able provide preferentialpharmacological release characteristics and profiles. It is a stillfurther advantage of the invention that the system control provided bythe systems allows for maximum control over the plasma concentrations ofthe delivered sufentanil, and therefore the therapeutic effect.

These and other objects, aspects and advantages of the present inventionwill readily occur to the skilled practitioner upon reading the instantdisclosure and specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents a cross-sectional view through a transdermal deliverysystem according to the present invention.

FIG. 2 presents a cross-sectional view through another transdermaldelivery system according to the present invention.

FIG. 3 present a schematic representation of a manufacturing process forproducing a transdermal delivery system according to the presentinvention.

FIG. 4 depicts the results from the Example 1 in vitro skin flux studyusing a transdermal delivery system according to the present invention.

FIGS. 5A and 5B depict the results from the Example 2 in vitro systemflux study using a transdermal delivery system according to the presentinvention.

FIG. 6 depicts the results from the Example 3 pharmacokinetic studyusing a transdermal delivery system having a drug releasing interfacesurface area of 1.42 cm².

FIG. 7 depicts the measured sufentanil plasma levels from Example 4 forthe test subjects wearing “thin” transdermal delivery systems.

FIG. 8 depicts the measured sufentanil plasma levels from Example 4 forthe test subjects wearing “thick” transdermal delivery systems.

FIG. 9 depicts the average sufentanil plasma levels for all four testgroups from Example 4.

FIG. 10 depicts the in vitro cumulative release data (with breathableoverlay) obtained in the Example 5 IVIVC study using the 2 and 8 cm²“thick” and “thin transdermal delivery systems.

FIG. 11 depicts the in vivo input data obtained in the Example 5 IVIVCstudy using the 2 and 8 cm² “thick” and “thin transdermal deliverysystems.

FIG. 12 depicts the in vitro and in vivo cumulative release dataobtained in the Example 5 IVIVC study using the 2 and 8 cm² “thick” and“thin transdermal delivery systems.

FIG. 13 depicts the in vitro and in vivo cumulative release dataobtained in the Example 5 IVIVC study using the 2 cm² “thick” and “thintransdermal delivery systems.

FIG. 14 depicts the in vitro and in vivo cumulative release dataobtained in the Example 5 IVIVC study using the 8 cm² “thick” and “thintransdermal delivery systems.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified materials or process parameters as such may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments of the inventiononly, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a polymer” includes a mixture of two or more suchmolecules, reference to “a solvent” includes a mixture of two or moresuch compositions, reference to “an adhesive” includes mixtures of twoor more such materials, and the like. In addition, whenever a specifiedrange is provided in the instant specification and claims, use of themodifier “about” is applied to all values or quantities specified bythat range. Thus, the phrase “about 1-12 wt %” means “about 1 to about12 wt %”, and the phrase “about 1-10 cm²” means “about 1 to about 10cm²”, and the like.

It is an object of the present invention to provide a transdermaldelivery system for administering sufentanil through the skin.

A transdermal delivery system for administering sufentanil through theskin was first suggested 1984 in U.S. Pat. No. 4,588,580 to Gale et al.The Gale et al. patent claims the transdermal patch technology employedin the commercial DURAGESIC® fentanyl transdermal patch product. Overthe course of the next twenty years, literally thousands of other patentapplications have been filed relating to a wide spectrum of transdermaldelivery technologies, transdermal patch design and components, andtransdermal delivery techniques. A large number of these new patentapplications have, like the Gale et al. patent, included the suggestionfor a sufentanil patch, but these suggestions are provided by way ofincluding the sufentanil agent in a long laundry list of drugs ratherthan by providing an enabling disclosure of how to actually design aproper sufentanil system. However, despite twenty years of suchsuggestions, there has never been a sufentanil patch that has enteredinto clinical testing.

The glaring absence of sufentanil transdermal systems from thepharmaceutical research and development and clinical landscapes, despiteboth the commercial success of a fentanyl patch and constant suggestionsfrom the patent literature, can be attributed to a number of featuresrelated to transdermal delivery in general and the sufentanil agent inspecific, all of which features are well recognized in the transdermalart. Initially, all transdermal delivery systems must overcome thenatural barrier to percutaneous absorption of an agent, which barrierfunction is naturally provided by the skin. The physical and chemicalproperties of any particular agent affect the degree to which that agentmay move across the skin barrier (the epidermis) via percutaneousabsorption, and thus agents can be characterized by their skinpermeation or epidermal permeability. Agents exhibiting a high degree ofskin permeation are good candidates for transdermal delivery systems,whereas agents exhibiting a low degree of skin permeation are generallyconsidered not to be good candidates.

There is also a very high degree of variability in the permeability ofhuman skin to any particular agent. In fact, skin permeability is knownto differ widely by region (e.g., skin from the thigh will havedifferent permeability than skin from the chest, and both will differfrom skin from the arm), by individual (e.g., the skin from differentindividuals will have different permeability), and even by specific sitewithin the same region (e.g., skin from different sites on a particularindividual's forearm will have different permeability). Shaw et al.(1991) in Physiology, Biochemistry, and Molecular Biology of the Skin,Second Ed., pp. 1447-1479, Goldsmith, L. A. Ed., Oxford UniversityPress, Oxford, UK. These variances are reported to be as much as 70%.Accordingly, it is not just a matter of overcoming the skin barrier,rather transdermal delivery system designs must also account for a widevariance in the degree to which an agent is able to traverse the skin.

Another inherent feature in transdermal delivery systems relates to therelationship between the skin surface area that the system releases theagent to (the target surface or drug releasing interface) and the amountagent that can be delivered from the system. Transdermal deliverysystems must maintain intimate contact with the target surface for theduration of treatment. Accordingly, there is a de facto upward limit onthe size for any transdermal system dictated by the size where a givenpatch will be prone to lifting and peeling from the target surface inresponse to normal flexing and movement by the individual. A reasonabletransdermal patch size generally has a drug releasing interface surfacearea of around 40 cm² or less. However, restricting the size of atransdermal delivery system in this manner limits the amount of agentthat can be delivered from that system. Accordingly, agents with poorskin permeability generally require larger patch sizes to bring agentdelivery rates up to acceptable levels.

With regard to the features of the sufentanil agent itself, it is wellknown that sufentanil has a very high potency, reported to be from7.5-15 times more potent than fentanyl. See U.S. Pat. No. 4,588,580 toGale et al. Sufentanil also has a relatively narrow therapeutic indexand, due to its very high potency, will produce highly undesirable sideeffects upon over dosage that can lead to death. Sufentanil is alsoreported to have extremely poor skin permeability, for example in theGale et al. patent it was noted that fentanyl has poor skin permeabilityand that sufentanil has even less permeability than fentanyl, and inU.S. Patent Publication No. US 2003/0026829 to Venkatraman et al., itwas noted that sufentanil is from 50 to 75% less permeable than fentanylin skin. Accordingly, the skilled transdermal artisan is faced withconflicting choices when considering the design of a sufentaniltransdermal delivery system. It would be expected that the amount ofsufentanil that can be delivered from a given system will be exceedinglylow due to the poor skin permeability of sufentanil. This in turnsuggests that techniques must be employed to increase sufentanil skinpermeability, for example by using permeation enhancers to increasedelivery to a sufficient rate to fit within the narrow therapeutic indexfor sufentanil. However, the side effect profile for sufentanil suggestsjust the opposite, where the possibility of overdose would lead todesign of a system that has a restricted delivery rate.

When the above-noted sufentanil-specific design considerations arecombined with considerations such as the need to reduce the affect ofskin variability on transdermal delivery system performance, it is nosmall wonder that an effective sufentanil transdermal delivery systemhas heretofore not been developed. The skilled artisan was left with thedesign concerns discussed above and two suggested approaches for atransdermal sufentanil system, appearing at either end of a two-decadelong period and providing two similar approaches to the problem. Thefirst suggestion for a sufentanil system was provided in U.S. Pat. No.4,588,580 to Gale et al. In this document, Gale et al. noted the lowskin permeability of both fentanyl and sufentanil. The two suggestionsfor system design that were provided by Gale et al. were to eitherprovide a matrix type system that delivered the agent for continuousperiods and had no system control (relying instead on skin permeabilityto control agent input rates), or preferably to provide a system wherethe system itself controls the maximum rate at which the agent isdelivered through the skin. In the second design that provides systemcontrol, Gale et al. taught that it is necessary to substantiallyincrease the flux of the agent (fentanyl or sufentanil) through the skinby use of a skin permeation enhancer. The second suggestion from Gale etal. was used to design the DURAGESIC® transdermal fentanyl system, wherea reservoir of the fentanyl agent is provided with a rate-limitingmembrane to provide a system-controlled patch. Alcohol is added to thereservoir as a permeation enhancer, where the alcohol serves to enhancefentanyl flux through the rate-limiting membrane and increase thepermeability of the skin to fentanyl. This selected design provides atransdermal delivery system that is able to deliver the fentanyl agentat acceptably high rates (due to the addition of a permeation enhancer),but net delivery is still highly variable, particularly from aninterindividual perspective (DURAGESIC® Fentanyl Transdermal SystemPackage Insert, 2004). Whereas such person-to-person variability may beacceptable in a fentanyl system, it would likely not be acceptable in asufentanil system due to safety considerations. The other alternativesuggested by Gale et al., that is, a system that relies solely on skinpermeability to control delivery rates, would likewise have unacceptablyhigh variability for a sufentanil system.

The second suggested approach for a sufentanil transdermal deliverysystem was provided almost 20 years after Gale et al. in U.S. PatentPublication No. US 2003/0026829 to Venkatraman et al. In this document,Venkatraman et al. noted the low skin permeability of both fentanyl andsufentanil, and in particular reported that sufentanil has from 50 to75% less skin permeability than fentanyl. It was also noted that thefentanyl and sufentanil agents required careful handling due to theirsafety profiles. The system design that is suggested for sufentanil usesa subsaturated system (where the sufentanil agent is present in anamount below the solubility limit of the agent in the selected system)monolithic matrix, wherein the system is not rate-controlled.Accordingly, the Venkatraman et al. transdermal system would be expectedto administer the sufentanil agent at a decreasing rate that isproportional to the level of saturation of the agent in the system, andrelies upon skin permeability to control the delivery rate. Thisapproach is generally the first approach suggested by Gale et al., thatis, a non-rate controlled system. Venkatraman et al. teach that asaturated system (e.g., depot system) would provide for a higher rate ofdelivery, but that their subsaturated system must nevertheless beselected. A review of in vitro data relating to delivery of sufentanilfrom the Venkatraman et al. system indicates that it provides a low netflux (for systems containing between 2-11% sufentanil, the net fluxranges from 0.1 to 0.9 μg/cm²/hour), and further that there issubstantial variability in the net delivery. Here again, it is believedthat whereas such variability may be suitable for a fentanyl transdermalsystem, it would not be suitable for a sufentanil transdermal deliverysystem.

Applicant has taken a substantial departure from these past suggestedapproaches, and has now developed a transdermal delivery system foradministering sufentanil through the skin, where the system ischaracterized by having a high degree of system control (dosage formrate control) over delivery of sufentanil from the system in spite ofalso having a high total net flux from the system through the skin witha particularly low variability (coefficient of variation). The presentdelivery systems are surprisingly able to provide these performancefeatures without the use of permeation enhancers.

From Shaw et al. (1985) “Transdermal Dosage Forms,” in Rate Control inDrug Therapy, (Prescott et al. eds), pp: 65-70, Churchill Livingstone,Edinburgh, it is known that in a rate controlled transdermal deliverysystem, the relation between the net flux (J_(N)), the flux through skin(J_(S)) and flux from the dosage form (J_(D)) can be given by thefollowing equation:

$\begin{matrix}{\frac{1}{J_{S}} = {\frac{1}{J_{S}} + \frac{1}{J_{D}}}} & ( {{Formula}\mspace{20mu} I} )\end{matrix}$

The relationship between the variability in net flux through the skinfrom the dosage form

$\frac{\Delta \; J_{N}}{J_{N}},$

the variability in skin flux

$\frac{\Delta \; J_{S}}{J_{S}},$

to the degree of dosage form rate control provided by the system, whichis defined as

$\frac{J_{N}}{J_{D}},$

an be represented by the following equation:

$\begin{matrix}{\frac{\Delta \; J_{N}}{J_{N}} = {\frac{\Delta \; J_{S}}{J_{S}}{( {1 - \frac{J_{N}}{J_{D}}} ).}}} & ( {{Formula}\mspace{14mu} {II}} )\end{matrix}$

As can be seen from the relationships represented by Formula I andFormula II, the ability to exert a high degree of dosage form ratecontrol in a transdermal delivery system can substantially eliminate theeffect that skin flux variability may have on the variability of netflux through the skin from the dosage form. The transdermal deliverysystems of the present invention are designed to provide a high degreeof dosage form rate control. Accordingly, in one embodiment of theinvention, a transdermal delivery system for administering sufentanilthrough the skin is provided. The system provides a dosage form ratecontrol over flux of sufentanil from the system and a net flux from thesystem through the skin of at least about 1 μg/cm²/hour. The system doesnot contain a permeation enhancer. In particular systems of theinvention, the dosage form rate control 134

$( \frac{J_{N}}{J_{D}} )$

is at least about 50%, in other systems it is at least about 60%, and instill other systems, it is at least about 65% or greater. The dosageform rate control can be provided by a number of differentmechanisms/components, either alone or in combination. For example, ratecontrol can be provided at least in part by using a pharmaceuticallyacceptable adhesive matrix carrier composition, wherein the materialsused to construct the matrix are selected so as to provide control overdelivery of the sufentanil agent from the transdermal delivery system.Alternatively, or in addition, a rate controlling membrane can be usedto provide control over delivery of sufentanil from the system.

In the instant transdermal delivery systems, the sufentanil agent can bepresent in the system in an amount of about 1-20 weight percent (wt %)relative to the total system, preferably in an amount of about 1-20 wt%, preferably in an amount of about 1-12 wt %. In certain systems, thesufentanil is provided as a depot, and is thus present in the system inan amount above the solubility of sufentanil in the system, such thatthere will be both dissolved and undissolved sufentanil in the system.In any regard, the transdermal delivery systems are provided withsufficient amount of the sufentanil agent to provide for a steady statenet flux sufficient to administer the sufentanil at from about 0.01 to200 μg/hour when the system is applied to the skin of a subject. Certainother systems of the present invention provide a steady state net fluxsufficient to administer sufentanil at from about 1 to 20 μg/hour whenthe system is applied to the skin of a subject, while still furthersystems are able to provide a steady state net flux sufficient toadminister sufentanil at from about 1 to 2 μg/hour.

The present transdermal delivery systems contain a sufficient amount ofsufentanil so that they may be used to induce and maintain a suitablestate of analgesia in a subject for 3 or more days when applied to theskin of that subject. Other systems contain a sufficient amount ofsufentanil to induce and maintain a suitable state of analgesia in asubject for 5 or more days, while still others contain enough to induceand maintain a suitable state of analgesia in a subject for 7 or moredays.

The long duration intended uses of the present transdermal deliverysystems impart further design considerations upon those systems.Particularly, the transdermal delivery systems must maintain intimatecontact with the target surface (drug releasing interface surface) forthe duration of treatment. A system that has insufficient adhesiveproperties and/or which is too rigid and nonflexible, will be prone todisplacement from the target skin surface, thereby interrupting or atleast reducing the intended rate of delivery of sufentanil from thesystem. A patch that is too large will also be prone to lifting andpeeling from the target surface in response to normal flexing andmovement by the individual. In addition, the adhesive properties of thesystem must take into account the changes in skin hydration broughtabout by normal daily activity, such as bathing or showering, andperspiring due to exercise or exertion.

Accordingly, the materials used in the construction of a transdermaldelivery system according to the present invention are selected toprovide a patch that has suitable drape, that is, flexibility so as tomaintain contact between the target skin surface and the drug releasinginterface of the system throughout normal movement, stretching andbending of the skin site. In those transdermal delivery systems that areprovided as a monolithic, matrix-type system (where the sufentanil isblended with an adhesive carrier composition, such as apressure-sensitive adhesive, to provide both a carrier matrix for thesufentanil as well as the means for affixing the system to the targetskin surface), the adhesive is selected to have a shear time within aspecified range of times deemed suitable for present systems.

More particularly, a Shear Time Measurement Test can be used to assessadhesive properties in a monolithic transdermal delivery systemconstructed according to the present invention. The Shear TimeMeasurement Test is conducted as follows. A bar formed from steel plateis provided. The bar is placed on a horizontal surface and the face ofthe bar is cleaned using an appropriate alcohol wipe (typically threetimes using methanol) and dried. A sample transdermal patch is providedhaving a ½″ width. A first end of the sample patch is applied to thecleaned surface of the bar so that the contact with the bar is ½″×½″(the sample is applied to the surface ½″ from the bottom of the bar).The second end of the sample patch hangs freely below the bar. A weightholder is attached to the free end of the sample patch. The bar is thensuspended at a suitable height using a support structure, such that theface of the bar with the patch adhered to it is completely vertical.Care is taken not to impart any peeling force on the sample patch duringthis set-up procedure. The test is then run by carefully attaching a 100g weight to the weight holder at the free end of the sample patch andrecording the time that it takes for the sample patch to completelyseparate from the face of the vertical test bar. An appropriate sheartime as determined by the Shear Time Measurement Test indicates that asample adhesive system has suitable skin adhesion properties andsuitable cold flow properties. A passing test result from the Shear TimeMeasurement Test is between about 1 to 40 minutes. Patches that adherefor longer periods of time will generally adhere too tightly to the skinsurface, giving rise to displacement under influence of normal movement.Patches that adhere for shorter periods of time will not have suitableadherence to remain in place. In preferred embodiments, the adhesivesystem should have a Shear Time Measurement Test result of between about2 and 20 minutes, and more preferably between about 5 and 15 minutes.

Accordingly, in an embodiment of the invention, a transdermal deliverysystem for administering sufentanil through the skin is provided. Thesystem is a matrix-type transdermal patch system, and includes apressure-sensitive adhesive matrix containing the sufentanil agent. Thesystem does not contain a permeation enhancer. The adhesive propertiesof the matrix are selected such that the system has a shear time of fromabout 1 to 40 minutes as determined using the Shear Time MeasurementTest. In the subject system, the adhesive matrix provides dosage formrate control over flux of sufentanil from the system. The systems arecharacterized by having a substantially high net flux of sufentanil fromthe system. In this regard, certain systems provide a net flux ofsufentanil from the system through the skin of at least about 1μg/cm²/hour, while other systems provide a net flux of at least about1.5 μg/cm²/hour. In certain preferred systems, the overall size of thetransdermal delivery system is kept to minimum, such that the adhesivematrix has a drug releasing interface surface area of from about 1-10cm². In certain systems, the sufentanil agent can be present in anamount of about 1-20 weight percent (wt %) relative to the total system,preferably in an amount of about 1-12 wt %. In certain other systems,the sufentanil is provided as a depot, and is thus present in the systemin an amount above the solubility of sufentanil in the system, such thatthere will be both dissolved and undissolved sufentanil in the system.The transdermal delivery systems are provided with sufficient amount ofthe sufentanil agent to provide for a steady state net flux sufficientto administer the sufentanil at from about 0.01 to 200 μg/hour when thesystem is applied to the skin of a subject. Certain other systems of thepresent invention provide a steady state net flux sufficient toadminister sufentanil at from about 1 to 20 μg/hour when the system isapplied to the skin of a subject, while still further systems are ableto provide a steady state net flux sufficient to administer sufentanilat from about 1 to 2 μg/hour.

The present adhesive transdermal delivery systems contain a sufficientamount of sufentanil so that they may be used to induce and maintain asuitable state of analgesia in a subject for 3 or more days when appliedto the skin of that subject. Other systems contain a sufficient amountof sufentanil to induce and maintain a suitable state of analgesia in asubject for 5 or more days, while still others contain enough to induceand maintain a suitable state of analgesia in a subject for 7 or moredays.

In one particular embodiment, the instant adhesive transdermal deliverysystems are provided as a dimensionally stratified family of transdermalpatches of varying doses, all having an adhesive matrix with a drugreleasing interface surface area of from about 1-10 cm². For example,the family can include four patches having drug releasing interfacesurface area of 2, 4, 6 and 8 cm², respectively, wherein the patchesrespectively contain 1, 2, 3 and 4 mg of the sufentanil agent. In thiscase, the size of the patch provides a visual clue to a health serviceprovider, possibly avoiding accidental application of a transdermaldelivery system containing an incorrect dose of sufentanil. In addition,the nested doses allow for convenient dosing of an individual, wherestep-wise incremental increases/decreases in the dose can be made withthe simple application/removal of one or more of the sized patches inthe family. The superior adhesive properties displayed by the instantadhesive systems further allow for in-clinic dose reduction procedures,where a particular patch (e.g., the 8 cm² patch containing 4 mg ofsufentanil) can be divided into halves, thirds or quarters, to provide adifferent, fully operable patch having a reduced size and therefore areduced dose of sufentanil (e.g., a 4 cm² patch with 2 mg sufentanil, ora 2 cm² patch with 1 mg sufentanil). In this regard, indicia may beprovided on the backing of the subject patches to facilitate accuratedivision of a particular patch into two or more patches of smaller sizeand dose.

It is a surprising feature of the transdermal delivery systems of thepresent invention that they are able to provide such high system controland high net flux of sufentanil from the systems without the use ofpermeation enhancers. It is even more surprising that transdermaldelivery systems displaying such high system control and net flux ofsufentanil can be provided in such small sizes, generally in the orderof about 20% the size of previous transdermal systems. Accordingly, inone embodiment, a transdermal delivery system for administeringsufentanil through the skin is provided. The system provides a dosageform rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system of at least about 50% whilestill allowing a net flux of sufentanil from the system through the skinof at least about 1 μg/cm²/hour. The system does not contain apermeation enhancer. In certain systems, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is even higher, for example atleast about 60%, while in still other systems the dosage form ratecontrol is at least about 65%. As with the other systems of the presentinvention, the dosage form rate control can be provided by a number ofdifferent mechanisms/components, either alone or in combination. Thus,the dosage form rate control can be provided at least in part by using apharmaceutically acceptable adhesive matrix carrier composition, whereinthe materials used to construct the matrix are selected so as to providecontrol over delivery of the sufentanil agent from the transdermaldelivery system. Alternatively, or in addition, a rate controllingmembrane can be used to provide control over delivery of sufentanil fromthe system. Despite such a high degree of system control in the presentsystems, certain systems are able to provide a net flux of sufentanilfrom the system through the skin of at least about 1.5 μg/cm²/hour,while still others can provide a net flux of around 2 μg/cm²/hour, allwithout the use of a permeation enhancer.

In certain high system control/high net flux systems, the sufentanilagent can be present in an amount of about 1-20 weight percent (wt %)relative to the total system, preferably in an amount of about 1-12 wt%. In certain other systems, the sufentanil is provided as a depot, andis thus present in the system in an amount above the solubility ofsufentanil in the system, such that there will be both dissolved andundissolved sufentanil in the system. The transdermal delivery systemsare provided with sufficient amount of the sufentanil agent to providefor a steady state net flux sufficient to administer the sufentanil atfrom about 0.01 to 200 μg/hour when the system is applied to the skin ofa subject. Certain other systems of the present invention provide asteady state net flux sufficient to administer sufentanil at from about1 to 20 μg/hour when the system is applied to the skin of a subject,while still further systems are able to provide a steady state net fluxsufficient to administer sufentanil at from about 1 to 2 μg/hour.

The present high system control/high net flux transdermal deliverysystems contain a sufficient amount of sufentanil so that they may beused to induce and maintain a suitable state of analgesia in a subjectfor 3 or more days when applied to the skin of that subject. Othersystems contain a sufficient amount of sufentanil to induce and maintaina suitable state of analgesia in a subject for 5 or more days, whilestill others contain enough to induce and maintain a suitable state ofanalgesia in a subject for 7 or more days.

It is another surprising feature of the transdermal delivery systems ofthe present invention that they are able to provide such high net fluxof sufentanil from the systems without the use of permeation enhancers,wherein the coefficient of variation in the net flux

$( \frac{\Delta \; J_{N}}{J_{N}} )$

is low, being held to about 50% or less. It is even more surprising thattransdermal delivery systems displaying such high net flux of sufentaniland such low variability in the net flux can be provided in such smallsizes, generally in the order of about 20% the size of previoustransdermal systems. Accordingly, in one embodiment, a transdermaldelivery system for administering sufentanil through the skin isprovided. When applied to a subject, the system provides a net flux ofsufentanil from the system through the skin of at least about 1μg/cm²/hour with a very low degree of variability in the net flux fromthe system, such that the coefficient of variation in the net flux

$( \frac{\Delta \; J_{N}}{J_{N}} )$

is about 50% or less. The system does not contain a permeation enhancer.

In certain preferred low variability systems, the subject system furtherprovides a dosage form rate control over flux of sufentanil form thesystem. More particularly, certain systems are further able to provide adosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system of at least about 50% whilestill providing a very low degree of variability in the net flux fromthe system. In certain systems, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is even higher, for example atleast about 60%, while in still other systems the dosage form ratecontrol is at least about 65%. As with the other systems of the presentinvention, the dosage form rate control can be provided by a number ofdifferent mechanisms/components, either alone or in combination. Thus,the dosage form rate control can be provided at least in part by using apharmaceutically acceptable adhesive matrix carrier composition and/or arate controlling membrane. Despite such a low degree of variability inthe net flux from the present systems, certain systems are able toprovide an even higher net flux of sufentanil from the system throughthe skin, on the order of at least about 1.5 μg/cm²/hour, while stillothers can provide a net flux of around 2 μg/cm²/hour, all without theuse of a permeation enhancer.

In certain low variability/high net flux systems, the sufentanil agentcan be present in an amount of about 1-20 weight percent (wt %) relativeto the total system, preferably in an amount of about 1-12 wt %. Incertain other systems, the sufentanil is provided as a depot, and isthus present in the system in an amount above the solubility ofsufentanil in the system, such that there will be both dissolved andundissolved sufentanil in the system. The transdermal delivery systemsare provided with sufficient amount of the sufentanil agent to providefor a steady state net flux sufficient to administer the sufentanil atfrom about 0.01 to 200 μg/hour when the system is applied to the skin ofa subject. Certain other systems of the present invention provide asteady state net flux sufficient to administer sufentanil at from about1 to 20 μg/hour when the system is applied to the skin of a subject,while still further systems are able to provide a steady state net fluxsufficient to administer sufentanil at from about 1 to 2 μg/hour.

The present low variability/high net flux transdermal delivery systemscontain a sufficient amount of sufentanil so that they may be used toinduce and maintain a suitable state of analgesia in a subject for 3 ormore days when applied to the skin of that subject. Other systemscontain a sufficient amount of sufentanil to induce and maintain asuitable state of analgesia in a subject for 5 or more days, while stillothers contain enough to induce and maintain a suitable state ofanalgesia in a subject for 7 or more days.

It is still another surprising feature of the transdermal deliverysystems of the present invention that a very small sized system can beused to induce and maintain analgesia for 3 or more days when applied toa subject, wherein the delivery efficiency at the end of the therapeuticperiod is at least about 70%, that is, at least about 70% of thesufentanil is delivered to the subject over the course of three days.The delivery efficiency, or system efficiency, for a given transdermaldelivery system at any point in time can be assessed by dividing themass of sufentanil delivered from the system at substantially zero orderby the total mass of sufentanil that was provided in the system at theinitiation of the administration. In addition, since the mass ofsufentanil provided in a new system is known, the delivery efficiencyfor a given patch removed from a subject after, e.g., a three dayadministration period, can be readily determined by extracting thesufentanil remaining in the system to determine the remaining mass ofsufentanil and then comparing this mass against the starting mass. Inthe present invention, the transdermal delivery systems are designedsuch that the sufentanil has a very low solubility in the system, thethickness of the reservoir in which the sufentanil is provided is keptto a minimum, and the overall system size is minimized as much aspossible. In addition, other controls over system efficiency can beused, such as where the sufentanil is added to a system in a tightlycontrolled particle size distribution.

Accordingly, in one embodiment, a transdermal delivery system foradministering sufentanil through the skin is provided. The systemincludes a reservoir containing a sufficient amount of sufentanil toinduce and maintain analgesia for 3 or more days when applied to asubject. The reservoir may be an adhesive or non-adhesive matrix, andhas a dry, non-hydrated thickness of about 1.25 to 5 mils. The systemprovides a delivery efficiency of at least about 50% of the sufentanilfrom the reservoir at the end of 3 or more days of application to asubject, preferably at least about 60%, and more preferably at leastabout 70%. In certain systems, the reservoir contains a sufficientamount of sufentanil to induce and maintain analgesia for 5 or more dayswhen applied to a subject while maintaining a delivery efficiency of upto at least about 70% at the end of the 5 days, and still other systemsinclude a reservoir that contains a sufficient amount of sufentanil toinduce and maintain analgesia for 7 or more days when applied to asubject while maintaining a delivery efficiency of up to at least about70% at the end of the 7 days. In certain other systems, the deliveryefficiency is even greater, for example, at least about 80% at the endof the application period. It is preferred that the overall system sizeof the instant high efficiency transdermal delivery systems is minimizedas much as possible. Accordingly, in preferred embodiments, the highefficiency systems include a reservoir having a drug releasing interfacesurface area of from about 1-10 cm². In still further preferredembodiments, the high efficiency systems have a substantially smallreservoir volume, for example a volume of about 0.2 ml or less. Incertain systems, the reservoir has a volume of from about 0.0025 to0.154 ml.

In certain systems, the reservoir in the high efficiency transdermaldelivery systems includes an adhesive matrix composition. In certainpreferred systems, the subject system further provides a dosage formrate control over flux of sufentanil form the system. More particularly,certain systems are further able to provide a dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system of at least about 50% whilestill providing a high delivery efficiency from the system. In certainsystems, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is even higher, for example atleast about 60%, while in still other systems the dosage form ratecontrol is at least about 65%. As with the other systems of the presentinvention, the dosage form rate control can be provided by a number ofdifferent mechanisms/components, either alone or in combination. Thus,the dosage form rate control can be provided at least in part by using apharmaceutically acceptable adhesive matrix carrier composition and/or arate controlling membrane. Additionally, certain other high efficiencysystems are also able to provide a relatively high net flux ofsufentanil from the system through the skin, for example at least about1 μg/cm²/hour in some systems, and at least about 1.5 μg/cm²/hour, oreven around 2 μg/cm²/hour in other systems. It is notable that in thesehigh efficiency/high flux systems, there is still no need to provide apermeation enhancer, and as such, certain of the instant systems do notinclude a permeation enhancer.

In certain of the instant high efficiency transdermal delivery systemsof the present invention, the sufentanil agent can be present in anamount of about 1-20 weight percent (wt %) relative to the total system,preferably in an amount of about 1-12 wt %. In certain other systems,the sufentanil is provided as a depot, and is thus present in the systemin an amount above the solubility of sufentanil in the system, such thatthere will be both dissolved and undissolved sufentanil in the system.The transdermal delivery systems are provided with sufficient amount ofthe sufentanil agent to provide for a steady state net flux sufficientto administer the sufentanil at from about 0.01 to 200 μg/hour when thesystem is applied to the skin of a subject. Still other systems of thepresent invention provide a steady state net flux sufficient toadminister sufentanil at from about 1 to 20 μg/hour when the system isapplied to the skin of a subject, while further systems are able toprovide a steady state net flux sufficient to administer sufentanil atfrom about 1 to 2 μg/hour.

The transdermal delivery systems of the invention may be provided aseither a liquid or gel reservoir-type or a matrix-type device. Both ofthese configurations will naturally include a backing layer thatprovides a protective outer surface for the devices, as well as arelease liner or layer that will cover the adhesive portion of thedevice that is used to affix the same to the skin of a subject. Therelease liner is removed prior to application, thereby exposing theadhesive portion of the device, which will typically be apressure-sensitive adhesive. Accordingly, referring to FIGS. 1 and 2, atransdermal patch device is generally indicated at 2. The deviceincludes a backing layer 4, a reservoir 6 that contains the sufentanilagent, and a release liner 8. The reservoir 6 may be a liquid or gelreservoir, or it may be a matrix carrier that can be self-adhesive ornon-adhesive. Referring specifically to FIG. 2, in those devices wherethe reservoir is either a liquid or gel reservoir, or a non-adhesivematrix, the device 2 will further comprise an adhesive layer 10 thatserves to adhere the device to the skin. The adhesive layer 10 isgenerally a drug-permeable adhesive that is applied over the reservoir.In some devices, a further layer 12 can be employed as a ratecontrolling membrane, where the layer is selected to provide forselective movement of the sufentanil agent through the layer.

The backing layer 4, which adheres to the drug-containing reservoir 6serves as the upper layer of the device during use and functions as theprimary structural element of the device. The backing layer is thustypically a sheet or film of a preferably flexible elastomeric materialthat is substantially impermeable to the sufentanil agent. This backinglayer 4 typically has a thickness of about 0.1 to 5 mils, preferablyabout 0.5 to 2 mils, and more preferably about 1 to 1.5 mils, and isgenerally a material that permits the device to follow the contours ofthe skin such that it can be worn comfortably on any skin area includingjoints or other areas of flexure. Accordingly, there is a reducedlikelihood of the device dislodging from the skin due to differences inthe flexibility or resiliency of the skin and the device, as well as inresponse to normal mechanical strain brought about by movement and thelike. The backing layer may further be a monolithic (single layer) or amulti-layer (multilaminate), and may further be a breathable orocclusive material comprising fabric. Most commonly, the backing layer 4will be a polymeric material, or a laminate of polymeric materials.Suitable materials include, but are not limited to, polyethylene,polypropylene, polyesters, polyurethanes, polyethylene vinyl acetate,polyvinylidene chloride, block copolymers such as PEBAX, polyvinylacetate, polyvinylidene chloride, polyurethane, ethylene vinyl acetate,polyethylene terephthalate, polybutylene terephthalate, coated paperproducts, metal or metalized sheets and the like, and any combinationsthereof.

In preferred embodiments, the backing layer 4 comprises a low-, medium-or high-density polyethylene material, or a polyester material. In aparticularly preferred embodiment, the backing layer comprises alaminate of polyethylene and aluminum vapor coated polyester (e.g.,SCOTCHPAK® 1109 Backing, available from 3M, St. Paul, Minn.), or alaminate of polyester and polyethylene/ethylene vinyl acetate (e.g.,SCOTCHPAK® 9733 Backing, available from 3M).

The reservoir 6 is disposed on the backing layer. The reservoir may beformed from any number of standard materials well known in the art. Inthose devices where the reservoir is a liquid or gel-type reservoir, anysuitable gelling agent may be used to form an aqueous gel system, forexample cellulose materials. In those devices where the reservoir is amatrix-type reservoir, it may be formed from any polymeric material inwhich sufentanil has some solubility within a desired solubility range,for example, a polyurethane, ethylene/vinyl acetate copolymer (EVA),polyacrylate, styrenic block copolymer, and the like. It is preferredthat the reservoir 6 is an adhesive type matrix, formed from apharmaceutically acceptable pressure sensitive adhesive, preferably apolyisobutylene, polyacrylate or a styrenic block copolymer-basedadhesive.

More particularly, in those embodiments of the invention where thetransdermal delivery system is provided as a monolithic, adhesive matrixdevice, the reservoir 6 can be formed from standard pressure sensitiveadhesives known in the art. Suitable pressure sensitive adhesives foruse in the practice of the invention thus include, but are not limitedto, polyacrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene,polybutadiene, styrenic block polymers, blends and combinations of theabove, and the like. Suitable styrenic block copolymer-based adhesivesinclude, but are not limited to, styrene-isoprene-styrene blockcopolymer (SIS), styrene-butadiene-styrene copolymer (SBS),styrene-ethylenebutene-styrene copolymers (SEBS), and di-block analogsthereof. Suitable acrylic polymers are comprised of a copolymer orterpolymer comprising at least two or more exemplary components selectedfrom acrylic acids, alkyl acrylates, methacrylates, copolymerizablesecondary monomers or monomers with functional groups. Examples ofmonomers include, but are not limited to, acrylic acid, methacrylicacid, methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate,acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethylacrylate, dimethylaminoethyl methacrylate, tert-butylaminoethylacrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate,methoxyethyl methacrylate, and the like. See, e.g., Satas (1989)“Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology,2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y. In apreferred embodiment, the pressure-sensitive adhesive is an acrylatehaving no functional groups or cross linkers (e.g., DURO-TAKO® 87-9301,available from National Starch & Chemical, Bridgewater, N.J.), or ablend of acrylate-vinylacetates having —COOH and —OH functional groups(DURO-TAK® 87-2051 and 87-2287, National Starch & Chemical).

In certain other preferred embodiments, the reservoir 6 is formed from amonolithic adhesive matrix containing a polyisobutylene material. Thepolyisobutylene preferably comprises a blend of a high molecular weightpolyisobutylene (about 450,000 to 2,100,000 viscosity average molecularweight) and a low molecular weight polyisobutylene (about 1,000 to450,000 viscosity average molecular weight). In the polyisobutylenecompositions of the present invention it is preferred that the highmolecular weight: low molecular weight polyisobutylene in thesecompositions are used in a ratio of from about 20:80 to about 70:30,preferably between about 40:60 to about 50:50.

In a particularly preferred embodiment, the pressure-sensitive adhesiveis a combination of low and high molecular weight polyisobutylene (PIB)polymers, for example, a high molecular weight PIB having a viscosityaverage molecular weight of about 1,100,000 (OPANOL® B100, availablefrom BASF, North Mount Olive, N.J.) and a low molecular weight PIBhaving a viscosity average molecular weight of about 50,000-55,000(OPPANOL® B 12, available from BASF). In another preferred embodiment,the pressure-sensitive adhesive is a combination of a high molecularweight PIB having a viscosity average molecular weight of about1,100,000 (VISTANEX® MM L-100, available from ExxonMobil, Houston, Tex.)and a low molecular weight PIB having a viscosity average molecularweight of about 50,000-55,000 (OPPANOL® B 11 SFN, available from BASF).

In practice, the material forming the reservoir 6 has a solubility forthe drug of about 1 wt % to about 25 wt % of the total reservoirmaterial; preferably about 2 wt % to about 20 wt %; more preferablyabout 4 wt % to about 15 wt %; and even more preferably about 6 wt % toabout 12 wt %. The reservoir 3, with or without the adhesive coating 6,has a thickness of about

The reservoir 6 further includes the sufentanil agent and may alsocontain other optional ingredients, such as carriers, vehicles,additives, excipients, stabilizers, dyes, diluents, plasticizers,tackifying agents, crystallization inhibitors, solubility enhancers,inert fillers, antioxidants, anti-irritants, vasoconstrictors and othermaterials without pharmacological activity that are suitable foradministration in conjunction with the transdermal delivery systems ofthe present invention. These optional materials are pharmaceuticallyacceptable in that they are nontoxic, do not interfere with delivery ofsufentanil from the system, and are not for any other reasonsbiologically or otherwise undesirable. If a pressure sensitive adhesiveis used in accordance with the present invention, this must also bepharmaceutically acceptable. Examples of illustrative materials includewater, mineral oil, silicone, inorganic gels, aqueous emulsions, liquidsugars, waxes, petroleum jelly, and a variety of other oils andpolymeric materials.

Accordingly, in certain transdermal delivery systems of the inventionwhere the reservoir is an adhesive matrix, the reservoir 6 comprises oneor more materials capable of improving its adhesive characteristics suchas by reducing quick tack (tackifying agents), reducing cold-flow,increasing viscosity, and/or toughening the matrix structure. Examplesof suitable materials include, but are not limited to, aliphatichydrocarbons; aromatic hydrocarbons; hydrogenated esters; polyterpenes;polybutenes, silicone dioxide, silica, hydrogenated wood resins;tackifying resins, aliphatic hydrocarbon resins made from cationicpolymerization of petrochemical feedstocks or the thermal polymerizationand subsequent hydrogenation of petrochemical feedstocks, rosin estertackifiers, mineral oil, polybutylmethacrylate, high molecular weightacrylates, and any combinations thereof.

In certain systems, the reservoir 6 comprises one or moreviscosity-enhancing agents that improve the adhesive properties of thedevice, for example by allowing for removal and replacement. Theviscosity-enhancing agent may further serve to reduce the abusepotential of the transdermal delivery system by preferentiallyassociating with the sufentanil agent to provide a highly viscouscomposition that resists extraction of the sufentanil agent undertypical abuse conditions (alcohol extraction). The material can be ahigh viscosity liquid carrier material (“HVLCM”) that is non-watersoluble, and has a viscosity of at least 5,000 cP, (and optionally atleast 10,000, 15,000; 20,000; 25,000 or even 50,000 cP) at 37° C. andthat does not crystallize neat under ambient or physiologicalconditions. The term “non-water soluble” refers to a material that issoluble in water to a degree of less than one percent by weight underambient conditions. A particularly preferred viscosity-enhancing agentis sucrose acetate isobutyrate (SAIB) or some other ester of a sugaralcohol moiety with one or more alkanoic acid moieties. These materialshave bioadhesive qualities.

In practice, a small amount of the SAIB or similar viscosity-enhancingagent is added to a pressure-sensitive material such as a PIB or acrylicadhesive base. Due to the low hydrophobicity and low surface tension ofthe SAIB material, this enables the resultant adhesive/viscosity agentmixture to retain pressure sensitive properties even after the systemhas been applied and removed from the skin surface a number of times.This in turn allows the subject wearing a long-duration patch to removethe device during showering or heavy exercise, and then reapply thedevice without losing adhesion.

In those systems where a plasticizer is utilized, the reservoir canfurther comprise a plasticizer material that is typically an inert,organic, apolar, nonvolatile hydrophobic liquid. In particular, theplasticizer may be a hydrophobic liquid. Suitable plasticizer materialsthus include, but are not limited to, various long-chain aliphaticesters and alcohols, including such materials as polybutene, mineraloil, linseed oil, octyl palmitate, squalene, squalane, silicone oil,isobutyl stearate, olive oil, isopropyl myristate, isostearyl alcohol,oleyl alcohol, and the like. Particularly preferred for use herein ispolybutene, for example IDOPOL® L-14 or H-100, available from BP Amoco,Naperville, Ill.), having a viscosity substantially equivalent to lightmineral oil.

In addition, the reservoir can include one or more filler materials.Suitable fillers include, but are not limited to, metal oxides,inorganic salts, synthetic polymers, clays and the like. The metaloxides may be silicon dioxide, zinc oxide, magnesium oxide, titaniumoxide, and calcium oxide. Inorganic salts can be calcium, magnesium andsodium carbonate, calcium and magnesium sulfate, calcium phosphate, andthe like. Synthetic polymers can include methacrylic resin, nylon,polyethylene, and the like. Suitable clay compounds include talc,bentonite and kaolin.

Referring again to FIGS. 1 and 2, the device 2 further comprises apeelable release liner 8. The release liner is a disposable element thatserves only to protect the device prior to application to the skin.Typically, the release liner is formed from a material impermeable tothe sufentanil agent and other components of the system, and is easilyremovable from the reservoir. Release liners can generally be made ofthe same materials as the backing layer. Suitable materials thus includea polymeric material that may be optionally metallized. Examples of thepolymeric materials include polyurethane, polyvinyl acetate,polyvinylidene chloride, polypropylene, polycarbonate, polystyrene,polyethylene, polyethylene terephthalate, polybutylene terephthalate,paper, and the like, and a combination thereof. In preferredembodiments, the protective layer comprises a siliconized polyestersheet, or has a fluoropolymer coating. Particularly preferred materialsare SCOTCHPAK® 9744 (available from 3M), and MEDIRELEASE® 2249(available from Mylan Tech., St. Paul, Minn.).

Referring now to FIG. 2, certain transdermal delivery systems of theinvention may include an adhesive layer 10 that serves to adhere thedevice 2 to the skin. The adhesive layer 10 is generally adrug-permeable pressure sensitive adhesive that is applied over thereservoir. Standard pressure sensitive adhesives are well known in theart. Suitable pressure sensitive adhesives for use in the adhesive layer10 thus include, but are not limited to, polyacrylates, polysiloxanes,polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic blockpolymers, blends and combinations of the above, and the like. Thesematerials are disclosed in greater detail hereinabove. The adhesivelayer may also serve the purpose of a rate controlling layer ormembrane. However, in some systems, a further layer 12 is added as arate controlling membrane. Suitable rate controlling membrane materialsare known in the art and include, but are not limited to, low to highdensity polyethylene, ethylene vinyl acetate, polyurethane, and styrenepoly-butadiene.

The sufentanil agent is incorporated into the transdermal deliverysystems of the present invention in a free base form. In particular, thechemical name for sufentanil is:N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide.The molecular weight of sufentanil base is 386.56, and it has thefollowing structural formula:

The sufentanil agent is added to the reservoir in an amount of fromabout 0.1 mg/cm² to about 2 mg/cm², preferably in an amount of fromabout 0.3 mg/cm² to about 0.8 mg/cm², and even more preferably in anamount of about 0.4 mg/cm² to about 0.7 mg/cm².

Although a number of different transdermal delivery systemconfigurations are suitable for use in practicing the current invention,it is preferred that the systems are provided as a monolithic device,where the sufentanil is contained in an adhesive matrix adhered to abacking layer. Accordingly, in one embodiment of the invention, amonolithic transdermal delivery system for administering sufentanilthrough the skin is provided. The system includes a pressure-sensitiveadhesive matrix that contains sufentanil in an amount above thesolubility of sufentanil in the matrix. When the system is applied to asubject, the system provides a substantially constant steady state netflux of sufentanil from the system through the skin of at least about 1μg/cm²/hour for at least about 24 hours. The system does not include apermeation enhancer or rate controlling membrane. Here again, it issurprising that such high net flux systems that do not employ apermeation enhancer or rate controlling membrane can still perform tosuch high standards, where upon achieving steady state conditions, thesystem provides at least a first order release rate profile such thatthe system achieves substantially zero order release to provide aconstant steady state flux of sufentanil from the system over anextended period of time. In certain systems, the system provides asubstantially constant steady state net flux of sufentanil from thesystem through the skin of at least about 1 μg/cm²/hour for at leastabout 36 hours

Additionally, certain systems are also able to provide an even highersteady state net flux net flux of sufentanil from the system through theskin, for example at least about 1.5 μg/cm²/hour in some systems, oreven around 2 μg/cm²/hour in other systems. In certain preferredsystems, the overall size of the transdermal delivery system is kept tominimum, such that the adhesive matrix has a drug releasing interfacesurface area of from about 1-10 cm².

In certain of the instant constant steady state flux transdermaldelivery systems of the present invention, the sufentanil agent can bepresent in an amount of about 1-20 weight percent (wt %) relative to thetotal system, preferably in an amount of about 1-12 wt %. Thetransdermal delivery systems are provided with sufficient amount of thesufentanil agent to provide for a steady state net flux sufficient toadminister the sufentanil at from about 0.01 to 200 μg/hour when thesystem is applied to the skin of a subject. Still other systems of thepresent invention provide a steady state net flux sufficient toadminister sufentanil at from about 1 to 20 μg/hour when the system isapplied to the skin of a subject, while further systems are able toprovide a steady state net flux sufficient to administer sufentanil atfrom about 1 to 2 μg/hour. The present systems contain a sufficientamount of sufentanil so that they may be used to induce and maintain asuitable state of analgesia in a subject for 3 or more days when appliedto the skin of that subject. Other systems contain a sufficient amountof sufentanil to induce and maintain a suitable state of analgesia in asubject for 5 or more days, while still others contain enough to induceand maintain a suitable state of analgesia in a subject for 7 or moredays.

In another related embodiment of the invention, a monolithic transdermaldelivery system for administering sufentanil through the skin isprovided. The system includes a pressure-sensitive adhesive matrix thatcontains sufentanil in an amount above the solubility of sufentanil inthe matrix. When the system is applied to a subject, the system providesa net flux of sufentanil from the system through the skin of at leastabout 1 μg/cm²/hour. The system provides a dosage form rate control overflux of sufentanil from the system, but the system does not include apermeation enhancer or rate controlling membrane. In these systems, thesufentanil is provided as a depot, and is thus present in the system inan amount above the solubility of sufentanil in the system, such thatthere will be both dissolved and undissolved sufentanil in the system.In certain systems, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is at least about 50% whilestill providing the substantially high rate of net flux from the system.In certain systems, the dosage form rate control

$( \frac{J_{N}}{J_{D}} )$

over flux of sufentanil from the system is even higher, for example atleast about 60%, while in still other systems the dosage form ratecontrol is at least about 65%. As with the other systems of the presentinvention, the dosage form rate control can be provided by a number ofdifferent mechanisms/components, either alone or in combination. Thus,the dosage form rate control can be provided at least in part by using apharmaceutically acceptable adhesive matrix carrier composition and/or arate controlling membrane. Despite not including a permeation enhanceror rate controlling membrane, certain systems are able to provide aneven higher net flux of sufentanil from the system through the skin, onthe order of at least about 1.5 μg/cm²/hour, while still others canprovide a net flux of around 2 μg/cm²/hour.

In certain of the subject monolithic systems, the sufentanil agent canbe present in an amount of about 1-20 weight percent (wt %) relative tothe total system, preferably in an amount of about 1-12 wt %. Theinstant transdermal delivery systems are provided with sufficient amountof the sufentanil agent to provide for a steady state net fluxsufficient to administer the sufentanil at from about 0.01 to 200μg/hour when the system is applied to the skin of a subject. Certainother systems of the present invention provide a steady state net fluxsufficient to administer sufentanil at from about 1 to 20 μg/hour whenthe system is applied to the skin of a subject, while still furthersystems are able to provide a steady state net flux sufficient toadminister sufentanil at from about 1 to 2 μg/hour. It is a surprisingfeature of the instant systems in that they can also provide asubstantially constant steady state net flux of sufentanil from thesystem through the skin for at least about 24 hours. Certain othersystems are further able to provide a substantially constant steadystate net flux (J_(N)) of sufentanil of at least about 1.5 μg/cm²/hour.Still others are able to provide a substantially constant steady statenet flux (J_(N)) of sufentanil for at least about 36 hours. In certainpreferred systems, the overall size of the transdermal delivery systemis kept to minimum, such that the adhesive matrix has a drug releasinginterface surface area of from about 1-10 cm².

The monolithic transdermal delivery systems contain a sufficient amountof sufentanil so that they may be used to induce and maintain a suitablestate of analgesia in a subject for 3 or more days when applied to theskin of that subject. Other systems contain a sufficient amount ofsufentanil to induce and maintain a suitable state of analgesia in asubject for 5 or more days, while still others contain enough to induceand maintain a suitable state of analgesia in a subject for 7 or moredays.

In yet a further related embodiment of the invention, a transdermaldelivery system for administering sufentanil through the skin of aliving subject is provided. The subject system provides a substantiallyconstant delivery rate of sufentanil over a single applicationadministration period of at least about 48 hours and the constantdelivery rate is sufficient to establish and maintain a plasmasufentanil concentration having a minimum to maximum ratio of about 1.8or less over the relevant administration period. In certain systems, thedelivery rate of sufentanil from the transdermal delivery system issubstantially zero order. In others, the delivery rate of sufentanil ischaracterized by a total decline or increase of about 5 to 6% over theadministration period, and preferably, the delivery rate of sufentanilis characterized by substantially no total increase or decrease over theadministration period. The subject transdermal delivery systems are ableto provide a delivery rate at steady state of at least about 1 μg/hr to10 μg/hr, and the administration period extends from at least about 48hours to 7 days. Additionally, all of the above-described transdermaldelivery systems of the present invention can be engineered to provide asubstantially constant delivery rate of sufentanil over a singleapplication administration period of at least about 48 hours, whereinthe constant delivery rate is sufficient to establish and maintain aplasma sufentanil concentration having a minimum to maximum ratio ofabout 1.8 or less over the relevant administration period.

All of the transdermal delivery systems of the present invention can bereadily manufactured using known techniques. For example, to producematrix-type systems, a solution of a suitable polymeric reservoirmaterial can be added to a double planetary mixer, followed by additionof desired amounts of the sufentanil base. Typically, the polymericreservoir material is an adhesive polymer, which can be solubilized inan organic solvent, e.g., ethanol, ethyl acetate, and hexane. Aftermixing has taken place for a suitable period of time to achieveacceptable uniformity of the ingredients, the resultant mixture can befeed into a casting die. In such cases, the matrix/sufentanil mixture iscast as a wet film onto a moving web or belt, which is drawn throughlines and a series of ovens are then used to evaporate the castingsolvent to acceptable residual limits. The dried reservoir film can thenbe laminated to a selected backing membrane that is wound onto take-uprolls. In subsequent operations, individual transdermal patches aredie-cut, separated and unit-packaged. In other processes, a reservoircan be formed using dry-blending and thermal film-forming usingequipment known in the art. Preferably, the materials are dry blendedand extruded using a slot die followed by calendering to an appropriatethickness.

When manufacturing certain preferred monolithic systems according to theinvention that include a polyisobutylene/polyisobutylene blend as thematrix, it is preferable to use a solvent for the polyisobutylene thatis a non-solvent for the sufentanil, such as low molecular weighthydrocarbon solvents like heptane, hexane, or cyclohexane. Preferably,the mixture of polyisobutylene compositions includes from about 65 to90% by weight of the solvent, more preferably from about 70 to about 85%by weight of the solvent.

A preferred manufacturing process for a monolithic transdermal deliverysystem prepared according to the invention is as follows. Pre-weighedamounts of both high and low molecular weight PIBs and polybutene areadded into glass vessels containing pre-measured amount of n-heptane andthe containers are sealed. The PIB fractions and polybutene in thesealed containers are completely dissolved in n-heptane at roomtemperature using magnetic stirring equipment. Mixing of the n-heptanepolymer solution may continue in case when one or more of the inactiveingredients needs to be added in the polybutene-PIB formulations.Typical mass ratios of the low molecular weight PIB, high molecularweight PIB, polybutene oil and n-heptane are: 1.23:1:2.1:10.1,respectively. Selective additives in small quantities can be added atthe expense of all other non-solvent materials in the solution.

A pre-weighed amount of sufentanil is added to the above n-heptanesolutions of polybutene-polyisobutylene and the sufentanil suspension ishomogeneously mixed for approximately 2 days for complete equilibrationof sufentanil and the vehicle, using magnetic stirring equipment at roomtemperature. Then, stirring action is stopped for approximately 15minutes, air bubbles are removed from the sufentanil suspension, whichis now ready to be transferred on a piece of release liner forprecision-thickness coating of the suspension using either a motorizedfilm applicator (Elcometer, Inc.) or precision glass plates and squaremultiple clearance applicators (Gardner PG&T Co.).

The wet suspension films on release liner section are air-dried forapproximately 20 minutes at room temperature and 30 minutes at 70° C. ina convection oven (Blue M Electric, CSP Series Class A Oven). The ovendried sufentanil suspension films coated on the release liner film(reservoir/release liner laminate) are cooled to room temperature and aprecut piece of the backing film is laminated onto the reservoir/releaseliner laminate, which is still sitting on a precision glass plates. Aaluminum roller (diameter: 1 in., length: 4 in.) or a piece oflamination equipment (Roll over Roll Coater, SciMac Scientific Machine)is used to aid the lamination step by squeezing and eliminating airpockets out of the reservoir/release liner laminates.

The final steps of the sufentanil transdermal delivery systemfabrication include die cutting the final laminates, using steel ruledies and a punch press (Schmidt Toggle Press, Schmidt Feintechnik Corp.)into required system size (Apex Die, Inc.). Appearance of the cut edgesof the systems is examined. The total thickness and weight of thesystems are determined using a pair of calipers (Mitutoyo Corp.) and aprecision balance, respectively and recorded.

The systems are then placed into aluminum foil pouches, and the openends of the pouches are heat sealed using an impulse heat sealer(Impulse Heat Sealer, Clamco). The pouches are labeled appropriately andcounted and recorded.

Referring now to FIG. 3, a flow diagram illustrating the systemmanufacturing steps, along with materials, tools and equipment that arerequired for each unit operation for the systems is provided.

Once the transdermal delivery systems are produced, they are used toprovide an extended period of analgesia in a subject using the followingmethods. The term “subject,” as used herein, is used interchangeablywith “individual” and refers to any vertebrate in which it is desired toprovide a state of analgesia. The term thus broadly refers to any animalthat is to be treated with the systems of the present invention, such asbirds, fish and mammals including humans. In certain embodiments, thesystems and methods of the present invention are suitable to providesustained analgesia in veterinary practice and animal husbandry, e.g.,birds and mammals, whenever a long-term state of analgesia is convenientor desirable. In certain cases, the compositions are particularly suitedfor used with companion animals such as dogs or cats, and additionallymay be used with horses. In preferred embodiments, the term “subject”intends a human subject. Furthermore, the term “subject” does not denotea particular age, and the present systems are thus suited for use withsubjects of any age, such as infant, adolescent, adult and senior agedsubjects.

A suitable transdermal delivery system containing sufentanil andprepared according to the present invention is applied to a clean, dryand preferably non-hairy area of skin on a subject, for example, theinner upper arm surface or upper buttock. It is intended that differentskin sites are chose for subsequent system applications. Uponapplication to the skin, the sufentanil in the reservoir of thetransdermal delivery system will diffuse into the skin where it isabsorbed into the bloodstream to produce a systemic analgesic effect.The onset of analgesia depends on various factors, such as, potency ofthe sufentanil, the solubility and diffusivity of sufentanil in theskin, the thickness of the target skin, the concentration of sufentanilin the device reservoir, and the like. Generally, the subject willexperience an adequate effect within about one to six hours of initialapplication. When continuous analgesia is desired, a depleted system isremoved and a fresh system applied to a new location. For example, the 3to 7 day systems of the present invention can be sequentially removedand replaced with a fresh system at the end of the administration periodto provide relief from chronic pain. Substantially uninterruptedsequential system applications can thus be used to maintain plasmasufentanil levels at a substantially constant level. Additionally, it iscontemplated that doses may be increased over time, and that concurrentuse of other analgesics may occur to deal with breakthrough pain.

EXAMPLES

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

Example 1 In Vitro Sufentanil Flux Through Human Skin

In-vitro permeation sufentanil flux studies were conducted with humanskin from cadaver donors (dermatomed full thickness). Thigh skin fromsixteen different donors was used in the experiments, with a minimum of5 replicate skin samples per donor (total n=82). Prior to the in vitroskin drug flux experiment, the skin tissue was examined under amagnifying glass for any defects such as pinholes. Excluding any damagedareas, the intact skin areas were cut into 1-inch circles. Monolithicadhesive matrix patches using a high molecular weight/low molecularweight polyisobutylene (PIB) blend for the adhesive was prepared asdescribed above. In the tests, a sufentanil transdermal delivery systemwas placed on the stratum corneum side of the pre-cut skin sample. Then,the assembly of system and pre-cut skin specimen was positioned on thetop edge of the receptor side of a modified Franz cell with the dermalside of the skin tissue facing the receptor chamber. The donor side ofthe Franz Cell was securely positioned over the skin/system assembly,and the receptor chamber was filled with citrate buffer at pH 5.0containing 0.01% sodium azide. The Franz cell with the test system wasequilibrated at 32o C for the duration of the experiment. Atpredetermined intervals (typically 6 hours, 1, 2, 3, 4, 5, 6 and 7days), the entire receptor solution was collected from the Franz celland refilled with fresh receptor medium. The receptor solutions wereassayed for sufentanil concentration using a HPLC chromatographicmethod. The cumulative delivery amount and skin drug flux werecalculated for each skin/test system assembly. FIG. 3 illustrates theactual sufentanil skin flux over 7 days through human cadaver specimensfrom the 16 different donors. The overall average sufentanil skin fluxwas approximately 1.9 μg/cm²/hr, with a coefficient of variation of 40%.

Example 2 In Vitro Sufentanil Flux From Transdermal Delivery System

A sufentanil transdermal delivery system having a drug releasinginterface surface area of 1 cm² or 1.42 cm² Monolithic adhesive matrixpatches, using a high molecular weight/low molecular weightpolyisobutylene (PIB) blend for the adhesive and containing sufentanilwere prepared as described above.

In the test, the sufentanil transdermal delivery system was heldadhesively on a stainless steel holder, having the drug releasingsurface of the patch facing up and immersable in release medium, andpositioned at the center of a USP Dissolution Apparatus II with 1 Lvessels. Accurately, 600 mL of degassed 0.005N sodium phosphate, pH 5.5buffer solution was placed in the vessels and maintained at 32° C. whilethe paddle speed was maintained at 50 rpm during the dissolutionexperiment.

At the preset time intervals of 1, 2, 4, 8, 12, 16, 24, 36, and 48hours, 1 mL portions of the dissolution medium was withdrawn from thevessels and dispensed into HPLC vials. The following conditions wereused for the sufentanil assay in the samples:

Mode: Isocratic Mobile Phase: A - 75% 0.1% triethylamine in H₂O(adjusted to pH = 3.0 with B - 25% 100% acetonitrile H₃PO₄) Stop Time:4.0 minutes Post time: None Column Temperature: 40° C. Flow Rate: 1.0mL/min UV Detection: 230 nm Injection Volume: 10 μL AutosamplerTemperature: ambient room temperature Retention time: 2 minutes

From the sufentanil concentration, total volume of the buffer solutionremaining in the vessels and time intervals, it was possible tocalculate the cumulative amounts of sufentanil dissolved or releasedfrom the patches over time, and dissolution rate or release rate ofsufentanil from the sample transdermal delivery systems were calculated.

The results from the dissolution rate test are presented in FIGS. 5A and5B, and provided below in Tables 1 and 2.

TABLE 1 Total Total Total Total Average % Amount of Amount of Amount ofAmount of Initial Sampling Sufentanil Sufentanil Sufentanil SufentanilSufentanil Time (μg) (μg) (μg) (μg) Loading (hours) Vessel 1 Vessel 2Vessel 3 Vessel 4 Average SD Released 0.5 59.5 59.81 58.10 4.66 56.714.75 6.56 1 137.48 146.58 142.16 140.91 141.78 3.76 16.39 2 236.93251.04 242.34 243.48 243.45 5.81 28.14 3 309.37 334.27 318.36 321.13320.78 10.30 37.08 4 371.07 399.54 387.28 386.72 386.15 11.67 44.64 6445.24 467.06 441.88 443.05 449.31 11.92 51.94 8 469.14 503.65 486.94486.77 486.62 14.09 56.26 12 513.76 553.54 518.40 520.91 526.66 18.1760.88 16 533.20 578.49 544.58 546.57 550.71 19.44 63.67 24 576.36 624.70583.73 587.56 593.09 21.58 68.57 36 622.85 673.35 621.61 632.56 637.5924.34 73.71 48 652.20 704.98 658.56 673.27 672.25 23.53 77.72

TABLE 2 Midpoint Rate Rate Rate Rate Time (μg/cm²/hr) (μg/cm²/hr)(μg/cm²/hr) (μg/cm²/hr) (hour) Vessel 5 Vessel 6 Vessel 7 Vessel 8Average SD 0.25 81.31 68.65 77.09 59.42 71.62 9.68 0.5 109.95 107.80123.80 115.59 114.28 7.14 1.5 73.84 70.74 74.89 70.86 72.58 2.10 2.558.57 48.24 55.33 59.41 55.39 5.08 3.5 40.21 37.21 43.66 33.42 38.624.35 5 22.76 21.60 23.56 20.22 22.03 1.45 7 12.68 11.32 10.90 14.2512.29 1.51 10 7.75 6.50 6.12 7.96 7.08 0.91 14 3.23 5.68 5.26 4.65 4.701.07 20 3.20 3.18 2.31 3.38 3.02 0.48 30 3.09 2.01 2.10 1.96 2.29 0.5342 2.08 1.64 1.44 2.34 1.88 0.41

Example 3 Pharmacokinetic Evaluation of Sufentanil Transdermal DeliverySystem Following a Single Application in Rats

Sufentanil transdermal delivery systems having a drug releasinginterface surface area of 1 cm² or 1.42 cm² (both of which containapproximately 0.67 mg sufentanil free base per cm²) were applied to 5each of male and female rats of 7 to 8 weeks old (CD (Crl:CD® (SD) 1 GSBR) from Charles River Labs). The systems were monolithic adhesivematrix patches, using a high molecular weight/low molecular weightpolyisobutylene (PIB) blend for the adhesive, and were prepared asdescribed above.

At least 16 hours before dosing, the back and shoulders of each animalwas shaved and the targeted application areas washed with water. Carewas taken not to abrade the skin. One of the transdermal deliverysystems was applied to the dorsal midline and held in contact with theskin by elastic wrap placed over the system and around the animal.During the course of the PK study, the animals were given ad libitumcertified rodent diet #8728C (Harlan Teklad, Inc) and water, and housedin a controlled environment, temperature of 18-26° C., a relativehumidity of 50±20% and a 12 hour light/12 hour dark cycle.

Blood samples (approximately 1 ml each) were collected from each animalat time 0 (before system application) and at 24, 48, 96 and 168 hoursafter application of the system. Blood was collected via jugularvenipuncture and transferred into tubes containing potassium EDTAanticoagulant.

Blood samples were maintained on wet ice, in chilled Kryoracks, or atapproximately 5° C. prior to centrifugation to obtain plasma.Centrifugation was carried out within 30 minutes of collection. Plasmasamples were transferred to a tube and were maintained on dry ice priorto storage at approximately −70° C.

Sufentanil in the plasma samples was assayed using HPLC. The analyticaltechnique for the determination of sufentanil in rat plasma was asfollows. Sufentanil in rat plasma was determined using a HPLC/MS/MSmethod in the positive electrospray mode. The analytical column was aYMC basic (50×2 mm, 5 u) with mass detection of the transitions387.4/238.0 amu for sufentanil and 337.4/188.0 amu for the internalstandard.

The results of the study are presented below in Table 3.

TABLE 3 Average Patch Size, No. of Plasma Conc. Standard Subjects SampleTime (pg/mL) Deviation % RSD  1.0 cm², 0 0 0 0 Male + Female 24 1232 65553 n = 9  48 1428 930 65 96 994 331 33 168 856 328 38 1.42 cm², 0 0 0 0Male + Female 24 1211 412 34 n = 10 48 1360 493 36 96 1235 384 31 168781 332 43

The data from the 1.42 cm² patch study are also depicted in FIG. 6. Ascan be seen, the plasma concentration of sufentanil, delivered from asingle transdermal delivery system, having a drug releasing interfacesurface area of 1.42 cm², increased to establish an approximate constantlevel starting at approximately 24 hours after the system applicationand continued to maintain the level for 168 hours (7 days). During thecourse of the 7-day delivery, the plasma concentrations of sufentanilfrom time 24-168 hours in male and female rats were approximately1,150±260 μg/ml and 1,140±270 μg/ml, respectively. There is nostatistically significant difference in the sufentanil plasmaconcentrations between the male and female rats, suggesting that bothdrug delivery rate from the system and pharmacokinetic parameters suchas systemic drug clearance do not differ significantly between the twosexes of the rats used in the PK study.

The variability of the sufentanil plasma concentrations is remarkablyand equally low in both male and female rats (coefficient of variationof approximately 23%), confirming the fact that not only the variabilityof systemic clearance of the drug in different rats is low but also mostimportantly rate controlled drug delivery through the skin of differentrats of both sexes from the sufentanil transdermal delivery system issignificantly high so as to reduce or virtually eliminate variability inskin sufentanil permeability between rats of both sexes.

Example 3 Preparation of Sufentanil Transdermal Delivery Systems

A series of 3-day and 7-day monolithic adhesive matrix patches, usingeither a high molecular weight/low molecular weight polyisobutylene(PIB) blend, or acrylic polymers for the adhesive are prepared asfollows. The systems include from 1 to 4 mg of sufentanil and areprepared to deliver in human subjects, depending on the system size,from about 90 to 360 μg sufentanil per day, from systems having a drugreleasing interface surface area of from 2 to 8 cm², respectively. Eachsystem is individually packaged in an aluminum foil pouch carrying anappropriate pharmaceutical label.

The components for the 7-day systems are listed in Table 4 below.

TABLE 4 Primary Secondary material/ Regulatory material/ RegulatoryComponents Vendor Status Vendor Status Notes Backing Film Scotchpak DMF# 2610 Scotchpak DMF # 1109 - laminate of 1109 Backing 9733 Backing14291 polyethylene and (3M) (3M) aluminum vapor coated polyester. 9733 -laminate of polyester and polyethylene/ethylene vinyl acetate. HighMolecular Oppanol B100 Conforms to Vistanex MM Conforms to Viscosityaverage Weight PIB (BASF) 21 CFR L-100 21 CFR molecular weight is(polyisobutylene) 172.615 (ExxonMobil) 172.615 approx. 1,100,000(chewing gum (chewing gum base). ISO base). 9001 Certified Low Oppanol BConforms to Oppanol B Conforms to Viscosity average Molecular 12 SFN 21CFR 11 SFN 21 CFR molecular weight is Weight PIB (BASF) 172.615 (BASF)172.615 approx. 50,000-55,000 (polyisobutylene) (chewing (chewing gumbase). gum base). ISO 9001 ISO 9001 Certified Certified PolybuteneIndopol L- DMF # Indopol H- DMF # Indopol L-14 is 14 (BP 17390 100 17390viscosity-equivalent to Amoco) (BP Amoco) light mineral oil, USP ReleaseLiner Scotchpak DMF # Medirelease DMF # 3M release liner has a 9744 (3M)15781 2249 14652 fluoropolymer coating (Mylan and Mylan's release Tech)liner has a silicone coating Pouch Polyester/ Conforms to Paper/Conforms to Approximately 2.75 in × foil appropriate polyester/appropriate 3.25 in (Technipaq) CFR foil CFR sections (Technipaq)sections Label Paper Label Not None Not Product and drug (Avery)applicable applicable names, system size, drug content, and code numberAdditional Colloidal NF Povidone/ USP/NF CSD grade is M5P or InactiveSilicone compendial Crospovidone compendial M5DP. Ingredients Dioxide(BASF) Povidone grade is (Cabot) Kollidon 30 or crospovidone grade isKollidon CL-M.

The components for the 3-day systems are listed in Table 5 below.

TABLE 5 Primary Secondary material/ Regulatory material/ RegulatoryComponents Vendor Status Vendor Status Notes Backing Scotchpak DMF #Scotchpak DMF # 1109 - laminate of Film 1109 2610 9733 14291polyethylene and aluminum Backing Backing vapor coated polyester. (3M)(3M) 9733 - laminate of polyester and polyethylene/ethylene vinylacetate. Acrylate Duro-Tak DMF # Duro-Tak DMF # 87-9301 has nofunctional 87-9301 7477 87-2051, 87- 7477 groups and no cross linkers.(National 2287 DMF # 87-2051 and 87-2287 have Starch & (National 7477COOH and OH functional Chemical) Starch & groups, respectively, andChemical) acrylate-vinylacetates. Release Scotchpak DMF # MedireleaseDMF # 3M release liner has a Liner 9744 (3M) 15781 2249 (Mylan 14652fluoropolymer coating and Tech) Mylan's release liner has a siliconecoating Pouch Polyester/ Conforms to Paper/ Conforms Approximately 2.75in × foil appropriate polyester/ to 3.25 in (Technipaq) CFR foilappropriate sections (Technipaq) CFR sections Label Paper Label Not NoneNot Product and drug names, (Avery) applicable applicable system size,drug content, and code number Additional Colloidal NF Povidone/ USP/NFCSD grade is M5P or M5DP. Inactive Silicone compendial Crospovidonecompendial Povidone grade is Kollidon Ingredients Dioxide (BASF) 30 orcrospovidone grade is (Cabot) Kollidon CL-M.

Example 4 In vivo Pharmacokinetic Study with 7-Day SufentanilTransdermal Delivery Systems

Two Sufentanil transdermal delivery systems (patches) were produced, intwo sizes each with active surface areas of 2 and 8 cm², and used in aclinical pharmacokinetic performance study. The transdermal patches wereproduced as 7-day systems using the “primary” material components asdescribed in Table 4 above. In particular, the formulation used toproduce the transdermal patches was a follows (on a percentage of totaldry weight): Oppanol B100 (15.4%); Oppanol B12 SFN (22.0%); IndopolPolybutene L-14 (48.5%); CAB-O—Sil M-5P (6.4%); and sufentanil (7.7%);with the final patches using a Scotchpak #9744 release liner (3M) and aScotchpak #1109 backing material (3M). The two sizes of patches wereidentical in all aspects except that the casting thicknesses weredifferent; that is, “thin” patches were produced having a nominal 15 mil(wet) coating thickness of the bulk matrix/drug formulation, and “thick”patches were produced having a nominal 25 mil (wet) coating thickness ofthe same bulk formulation. The amount of sufentanil present in thepatches was proportional to the casting thicknesses, and therefore“thin” patches had a lower sufentanil drug content per square cmcompared to the “thick” patches. The average sufentanil content perpatch determined at the time of lot release for the thin and thicksufentanil patch lots, 2 cm² and 8 cm² sizes, used in the present studyare summarized in Table 6. As can be seen, the thick 2 cm² and 8 cm²patches had at least about 75% higher sufentanil content compared to thecorresponding thin 2 cm² and 8 cm² patches.

TABLE 6 Sufentanil TTS Descriptions and Observed Sufentanil ContentFormulation Observed Sufentanil Lot Code Patch Size Nominal Casting (mg)per Patch at Number Number (cm²) Thickness T = 0 (n = 10) 24A 45-01 2 15mil, thin 0.91 25A 47-01 2 25 mil, thick 1.70 24B 45-02 8 15 mil, thin3.84 25B 47-02 8 25 mil, thick 6.71

The study was performed in 24 healthy human volunteers, broken up intofour test groups of 6 individuals each (n=6), wherein the sufentanilpatches were applied to the chest of the subjects that had been blockedwith naloxone. In order to ensure that the patches remained in place,breathable overlay tape was used for each subject. The study wasinitiated with a low dose intravenous (IV) infusion of sufentanil (48μg/6 hours) followed by application of the 2 cm² thick and thin patches,or a high dose IV infusion of sufentanil (192 μg/6 hours) followed byapplication of the 8 cm² thick and thin patches. The patches were leftin place for 7 days and individual plasma sufentanil levels for eachtest subject were assessed periodically over the 7-day study periodusing standard LC/MS methodologies. The individual sufentanil plasmalevels observed for the subjects that wore the 2 cm² patches arereported in Table 7 below, and the individual sufentanil plasma levelsobserved for the subjects that wore the 8 cm² patches are reported inTable 8 below. The average and standard deviation sufentanil plasmalevels for all four of the test groups are reported in Table 9 below,and the average plasma levels across days 1-7 of the study are reportedin Table 10 below. FIG. 7 depicts the measured sufentanil plasma levelsfor the subjects that wore the thin patches, and FIG. 8 depicts themeasured sufentanil plasma levels for the subjects that wore the thickpatches. Finally, FIG. 9 depicts the average sufentanil plasma levelsfrom all four test groups.

TABLE 7 Sufentanil Plasma Levels in Normal Volunteers after Applicationof Sufentanil TTS for 7 Days Lot 24A, 2 cm² - Thin Patches Lot 25A, 2cm² - Thick Patches Time Time Subject Subject Subject Subject SubjectSubject Subject Subject Subject Subject Subject Subject (Hours) (Days) 12 3 4 5 6 7 8 9 10 11 12 0 0.00 0 0 0 2.83 3.05 2.10 0 0 0 0 2.03 0 40.17 4.27 5.06 0 2.66 8.12 4.28 5.71 2.15 2.82 3.07 5.52 4.30 8 0.3313.6 13.2 5.61 4.91 26.2 5.72 14.2 11.6 15.8 8.83 15.6 14.9 16 0.67 18.326.7 11.4 16.7 30.6 11.3 18.4 23.5 18.6 15.9 15.6 20.0 24 1.00 26.4 33.620.7 23.5 54.3 14.4 22.8 30.0 28.5 16.9 27.0 22.7 28 1.17 22.8 32.5 22.924.4 34.0 20.0 22.6 32.0 27.8 17.6 27.1 26.0 32 1.33 20.5 26.2 20.4 32.533.1 13.9 19.8 31.6 31.8 19.7 27.4 23.9 36 1.50 22.3 25.3 29.3 31.9 35.220.9 20.8 32.6 27.9 20.3 28.9 27.0 40 1.67 17.6 23.1 19.0 36.5 33.5 19.621.8 28.8 29.4 16.7 24.0 35.1 48 2.00 23.3 32.2 25.9 40.7 48.4 19.0 22.134.2 33.2 16.1 33.9 23.4 52 2.17 18.9 32.5 25.9 42.4 47.9 24.0 32.2 35.737.9 20.2 30.3 25.5 56 2.33 22.9 43.1 31.5 33.7 45.3 21.7 26.5 37.3 34.120.6 30.6 19.6 60 2.50 17.8 36.5 22.8 35.8 39.9 14.2 21.6 32.5 31.8 20.530.0 23.4 64 2.67 22.8 36.1 25.3 43.2 34.1 18.9 21.8 33.2 26.5 20.0 29.418.5 72 3.00 21.8 29.3 25.8 56.0 43.3 25.4 19.3 39.3 36.2 17.1 30.3 33.080 3.33 13.7 30.3 31.1 43.3 35.3 19.2 21.3 36.5 27.4 16.0 30.0 28.6 883.67 18.8 29.2 21.8 50.2 33.6 17.2 27.9 35.5 33.7 20.2 28.3 28.0 96 4.0013.3 31.1 37.0 54.2 39.0 32.8 16.9 37.0 33.4 21.0 33.1 30.8 104 4.3314.6 28.9 39.1 54.5 35.6 25.6 14.0 34.8 26.7 18.8 28.3 22.5 112 4.6712.0 26.3 26.8 39.4 31.4 26.2 23.4 27.4 31.2 19.8 26.9 20.7 120 5.0018.7 31.3 27.6 56.1 40.8 21.2 24.9 32.8 23.5 21.5 32.6 23.5 128 5.3311.4 36.9 28.3 44.2 35.4 16.3 21.8 33.2 23.6 19.9 30.5 18.9 136 5.6713.9 24.1 28.3 33.2 31.7 15.4 23.4 28.4 29.1 19.9 25.7 15.8 144 6.0015.5 29.0 27.1 41.8 39.2 26.8 15.1 31.9 33.2 17.8 28.3 24.2 152 6.3318.0 29.0 27.5 41.7 35.5 22.3 16.5 26.4 16.9 19.5 23.4 24.1 160 6.6712.6 26.3 23.3 36.9 36.6 22.1 21.2 30.6 19.9 22.7 23.7 24.7

TABLE 8 Sufentanil Plasma Levels in Normal Volunteers after Applicationof Sufentanil TTS for 7 Days Lot 24B, 8 cm² - Thin Patches Lot 25B, 8cm² - Thick Patches Time Time Subject Subject Subject Subject SubjectSubject Subject Subject Subject Subject Subject Subject Hours Days 13 1415 16 17 18 19 20 21 22 23 24 0 0.00 4.93 3.87 6.26 2.78 8.02 4.76 4.207.02 5.66 9.61 5.69 9.06 4 0.17 12.6 10.9 6.82 14.8 21.9 18.8 15.7 34.310.1 18.9 39.9 8 0.33 57.2 38.3 12.1 40.9 60.1 60.7 47.8 67.2 47.1 36.1205 142 16 0.67 83.1 86.3 58.0 83.9 68.0 88.2 78.3 94.2 102 73.7 93.7126 24 1.00 79.1 145 91.9 74.8 78.5 150 106 81.0 124 135 108 163 28 1.17112 110 90.0 98.4 112 110 116 91.7 127 108 132 152 32 1.33 101 113 97.7113 85.2 121 114 99.5 126 138 152 190 36 1.50 103 118 94.6 99.0 93.8 137109 104 137 150 125 152 40 1.67 89.0 108 110 128 95.4 120 101 89.3 150128 122 170 48 2.00 99.7 131 96.4 96.1 89.3 127 110 92.7 157 124 145 18952 2.17 97.3 112 120 107 82.8 123 110 111 178 136 106 158 56 2.33 11294.7 115 149 87.4 135 94.7 108 156 129 159 180 60 2.50 113 91.8 108 95.293.6 130 88.3 88.9 120 118 112 149 64 2.67 117 94.3 122 138 99.3 128 10974.6 138 107 157 135 72 3.00 116 113 116 118 89.7 103 91.9 105 140 199116 180 80 3.33 99.3 96.4 124 147 95.2 120 89.9 93.3 132 200 131 155 883.67 98.9 104 105 117 94.8 86.0 83.6 80.1 113 155 133 135 96 4.00 119130 107 127 88.2 93.5 103 83.6 141 197 150 134 104 4.33 105 103 124 13393.1 79.0 87.6 80.3 135 186 174 150 112 4.67 94.4 95.6 114 143 80.9 65.497.1 73.1 129 243 149 150 120 5.00 113 88.5 150 108 86.2 92.2 105 88.8160 326 155 140 128 5.33 106 103 150 139 88.1 96.4 81.6 67.6 114 300 160148 136 5.67 90.1 79.0 127 112 69.1 77.4 83.2 59.4 93.0 280 120 107 1446.00 82.8 93.1 167 146 66.0 96.0 98.8 70.9 128 310 148 111 152 6.33 85.486.8 117 135 89.4 61.4 69.2 75.5 108 342 128 104 160 6.67 79.8 85.9 102153 76.3 70.1 76.2 63.0 125 246 136 106

TABLE 9 Average Plasma Levels for Sufentanil TT Lot 24A, 2 cm² Lot 25A,2 cm² Lot 24B, 8 cm² Lot 25B, 8 cm² Time Time Thin Patches Thick PatchesThin Patches Thick Patches (Hours) (Days) Average SD Average SD AverageSD Average SD 0 0.00 1.3 1.5 0.3 0.8 5.1 1.8 6.9 2.1 4 0.17 4.1 2.7 3.91.5 14.3 5.5 23.8 12.7 8 0.33 11.5 8.2 13.5 2.7 44.9 18.8 90.9 67.8 160.67 19.2 8.0 18.7 2.9 77.9 12.1 94.7 18.7 24 1.00 28.8 14.0 24.7 4.8103.2 34.8 119.5 28.1 28 1.17 26.1 5.7 25.5 4.9 105.4 9.1 121.1 20.8 321.33 24.4 7.6 25.7 5.5 105.2 13.0 136.6 31.9 36 1.50 27.5 5.6 26.3 4.8107.6 16.9 129.5 20.4 40 1.67 24.9 8.1 26.0 6.5 108.4 14.6 126.7 30.0 482.00 31.6 11.2 27.2 7.7 106.6 17.7 136.3 34.7 52 2.17 31.9 11.3 30.3 6.6107.0 15.0 133.2 29.7 56 2.33 33.0 9.9 28.1 7.2 115.5 23.4 137.8 32.8 602.50 27.8 10.9 26.6 5.4 105.3 14.8 112.7 22.6 64 2.67 30.1 9.2 24.9 5.8116.4 16.8 120.1 29.2 72 3.00 33.6 13.3 29.2 9.1 109.3 11.0 138.7 42.980 3.33 28.8 10.8 26.6 7.1 113.7 20.5 133.5 41.0 88 3.67 28.5 12.4 28.95.4 101.0 10.5 116.6 30.1 96 4.00 34.6 13.3 28.7 7.9 110.8 17.5 134.839.4 104 4.33 33.1 13.5 24.2 7.4 106.2 19.8 135.5 43.8 112 4.67 27.0 8.924.9 4.4 98.9 27.0 140.2 £8.7 120 5.00 32.6 13.9 26.5 4.9 106.3 24.0162.5 84.9 128 5.33 28.8 12.7 24.7 5.9 113.8 24.8 145.2 83.9 136 5.6724.4 8.2 23.7 5.1 92.4 22.5 123.8 79.3 144 6.00 29.9 9.5 25.1 7.4 108.539.2 144.5 85.2 152 6.33 29.0 8.6 21.1 4.1 95.8 26.1 137.8 102.4 1606.67 26.3 9.3 23.8 3.7 94.5 30.6 125.4 65.3

TABLE 10 Average Plasma Values for Sufentanil TTS from Days 1 to 7 LotAverage Lot Number Description (pg/mL) SD 24A 2 cm², thin 29.2 10.1 25A2 cm², thick 25.9 5.9 24B 8 cm², thin 105.0 21.1 25B 8 cm², thick 133.351.7

As can be seen by a review of the data presented in Tables 7-10, thereis no significant difference in the sufentanil plasma levels achievedbetween the 2 cm² transdermal patches, even though the thick patches(Lot 25A) had about 75% greater sufentanil drug content as compared withthe thin patches (Lot 24A). This same observation can be made withregard to the 8 cm² transdermal patches. As can also be seen with regardto the data depicted in FIGS. 7-9, the in vivo flux of sufentanil fromthe patches (both thick and thin) remained essentially constant across asingle application administration period of at least about 7 days.Furthermore, with regard to the data presented in Tables 7-10, it can beseen that the transdermal patches were able to provide a substantiallyconstant delivery rate of sufentanil over a single applicationadministration period of at least about 48 hours to up to 7 days, wherethat constant delivery rate was sufficient to establish and maintain aplasma sufentanil concentration having a minimum to maximum ratio ofabout 1.8 or less over the relevant administration period.

Example 5 In vitro/In vivo Correlation Study for 7-Day SufentanilTransdermal Delivery Systems

In order to assess whether in vitro flux data obtained using the methodsdescribed in Examples 1 and 2 are predictive of the in vivo performanceof the sufentanil transdermal delivery systems of the present inventionas determined in Example 4 (in vitro/in vivo correlation, or “IVIVC”),the following modeling study was carried out. Since for many of the invivo test subjects, detectable sufentanil concentrations were present atthe time of the transdermal patch application (data not shown), theIVIVC model needed to account for such starting conditions to determinethe input from the transdermal delivery systems. A compartmentalmodeling approach was used. With regard to the data, there was a need inthe modeling to make an assumption regarding the structure of thetransdermal delivery system input function (unlike a conventionaldeconvolution). Based upon a preliminary deconvolution, a 4 knot splinefunction was selected that allowed for both an initial lag and change indelivery rate over the 7 day duration of the in vivo studies. Thus, foreach intravenous infusion (IV)/transdermal delivery system combination,the IV and the transdermal delivery data were modeled simultaneouslyusing a two-compartment PK model. The typical input function from thetransdermal delivery system was obtained, and correlated with in vitrocumulative release data obtained using the methods of Examples 1 and 2to assess the thin and thick 2 and 8 cm² patches used in the in vivostudies described in Example 4. In order to remain consistent, the samebreathable overlay tape used in the Example 4 studies was applied overthe transdermal delivery systems placed on the Franz cell apparatus. Theresults of the IVIVC modeling study are depicted in FIGS. 10-14. As canbe seen by a review of FIGS. 10-14, the in vitro cadaver skin flux dataobtained using the methods of Examples 1 and 2 is representative of thein vivo input from the transdermal delivery systems of the presentinvention. In this regard, the average skin flux of sufentanil observedin vivo for the 2 and 8 cm² patches is approximately 1.1 μg/cm²/hour.

1-25. (canceled)
 26. A transdermal delivery system for administeringsufentanil through the skin, wherein said system provides a dosage formrate control over flux of sufentanil from the system and a net flux ofsufentanil from the system through the skin of at least about 1μg/cm²/hour, and further wherein said system does not contain apermeation enhancer. 27.-60. (canceled)
 61. A transdermal deliverysystem for administering sufentanil through the skin, wherein saidsystem provides a net flux of sufentanil from the system through theskin of at least about 1 μg/cm²/hour with a coefficient of variation(ΔJ_(N)/J_(N)) of about 50% or less when applied to a subject, andfurther wherein said system does not contain a permeation enhancer.62.-100. (canceled)
 101. A monolithic transdermal delivery system foradministering sufentanil through the skin, said system comprising apressure-sensitive adhesive matrix containing sufentanil in an amountabove the saturation point of sufentanil in the matrix, wherein whenapplied to a subject, the system provides a net flux of sufentanil fromthe system through the skin of at least about 1 μg/cm²/hour, and furtherwherein the system provides a dosage form rate control over flux ofsufentanil from the system but does not include a permeation enhancer orrate controlling membrane. 102.-112. (canceled)
 113. The transdermaldelivery system of claim 26, wherein said system comprises apressure-sensitive adhesive matrix containing a polyisobutylenematerial.
 114. The transdermal delivery system of claim 113, wherein thepolyisobutylene material comprises a blend of high molecular weightpolyisobutylene and a low molecular weight polyisobutylene.
 115. Thetransdermal delivery system of claim 114, wherein the high molecularweight polyisobutylene has a viscosity average molecular weight of about450,000 to 2,100,000.
 116. The transdermal delivery system of claim 115,wherein the high molecular weight polyisobutylene has a viscosityaverage molecular weight of about 1,100,000.
 117. The transdermaldelivery system of claim 114, wherein the low molecular weightpolyisobutylene has a viscosity average molecular weight of about 1,000to 450,000.
 118. The transdermal delivery system of claim 117, whereinthe low molecular weight polyisobutylene has a viscosity averagemolecular weight of about 50,000 to 55,000.
 119. The transdermaldelivery system of claim 61, wherein said system comprises apressure-sensitive adhesive matrix containing a polyisobutylenematerial.
 120. The transdermal delivery system of claim 119, wherein thepolyisobutylene material comprises a blend of high molecular weightpolyisobutylene and a low molecular weight polyisobutylene.
 121. Thetransdermal delivery system of claim 120, wherein the high molecularweight polyisobutylene has a viscosity average molecular weight of about450,000 to 2,100,000.
 122. The transdermal delivery system of claim 121,wherein the high molecular weight polyisobutylene has a viscosityaverage molecular weight of about 1,100,000.
 123. The transdermaldelivery system of claim 120, wherein the low molecular weightpolyisobutylene has a viscosity average molecular weight of about 1,000to 450,000.
 124. The transdermal delivery system of claim 123, whereinthe low molecular weight polyisobutylene has a viscosity averagemolecular weight of about 50,000 to 55,000.
 125. The transdermaldelivery system of claim 101, wherein said pressure-sensitive adhesivematrix contains a polyisobutylene material.
 126. The transdermaldelivery system of claim 125, wherein the polyisobutylene materialcomprises a blend of high molecular weight polyisobutylene and a lowmolecular weight polyisobutylene.
 127. The transdermal delivery systemof claim 126, wherein the high molecular weight polyisobutylene has aviscosity average molecular weight of about 450,000 to 2,100,000. 128.The transdermal delivery system of claim 127, wherein the high molecularweight polyisobutylene has a viscosity average molecular weight of about1,100,000.
 129. The transdermal delivery system of claim 126, whereinthe low molecular weight polyisobutylene has a viscosity averagemolecular weight of about 1,000 to 450,000.
 130. The transdermaldelivery system of claim 129, wherein the low molecular weightpolyisobutylene has a viscosity average molecular weight of about 50,000to 55,000.